Excitatory amino acid receptor antagonists

ABSTRACT

The present invention provides novel compounds of Formula (I) and Formula (I(a)), or the pharmaceutically acceptable salts thereof; methods for treating neurological disorders and neurodegenerative diseases, particularly pain and migraine, comprising administering a compound of Formula (I) or Formula (I(a)); and processes for preparing compounds of Formula (I) or Formula (I(a)).

BACKGROUND OF THE INVENTION

In the mammalian central nervous system (CNS), the transmission of nerveimpulses is controlled by the interaction between a neurotransmitter,that is released by a sending neuron, and a surface receptor on areceiving neuron, which causes excitation of this receiving neuron.L-Glutamate, which is the most abundant neurotransmitter in the CNS,mediates the major excitatory pathways in mammals, and is referred to asan excitatory amino acid (EAA). The receptors that respond to glutamateare called excitatory amino acid receptors (EAA receptors). See Watkins& Evans, Ann. Rev. Pharmacol. Toxicol., 21, 165 (1981); Monaghan,Bridges, and Cotman, Ann. Rev. Pharmacol. Toxicol., 29, 365 (1989);Watkins, Krogsgaard-Larsen, and Honore, Trans. Pharm. Sci., 11, 25(1990). The excitatory amino acids are of great physiologicalimportance, playing a role in a variety of physiological processes, suchas long-term potentiation (learning and memory), the development ofsynaptic plasticity, motor control, respiration, cardiovascularregulation, and sensory perception.

Excitatory amino acid receptors are classified into two general types.Receptors that are directly coupled to the opening of cation channels inthe cell membrane of the neurons are termed “ionotropic.” This type ofreceptor has been subdivided into at least three subtypes, which aredefined by the depolarizing actions of the selective agonistsN-methyl-D-aspartate (NMDA),α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainicacid (KA). Molecular biological studies have established that AMPAreceptors are composed of subunits (GluR₁-GluR₄), which can assemble toform functional ion channels. Five kainate receptors have beenidentified which are classified as either High Affinity (KA1 and KA2) orLow Affinity (composed of GluR₅, GluR₆, and/or GluR₇ subunits). Bleakmanet al., Molecular Pharmacology, 49, No.4, 581,(1996). The second generaltype of receptor is the G-protein coupled or second messenger-linked“metabotropic” excitatory amino acid receptor. This second type iscoupled to multiple second messenger systems that lead to enhancedphosphoinositide hydrolysis, activation of phospholipase D, increases ordecreases in cAMP formation, and changes in ion channel function.Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). Both typesof excitatory amino acid receptor appear not only to mediate normalsynaptic transmission along excitatory pathways, but also to participatein the modification of synaptic connections during development andthroughout life. Schoepp, Bockaert, and Sladeczek, Trends in PharmacolSci., 11, 508 (1990); McDonald and Johnson, Brain Research Reviews, 15,41 (1990).

The excessive or inappropriate stimulation of excitatory amino acidreceptors leads to neuronal cell damage or loss by way of a mechanismknown as excitotoxicity. This process has been suggested to mediateneuronal degeneration in a variety of neurological disorders andconditions. The medical consequences of such neuronal degeneration makesthe abatement of these degenerative neurological processes an importanttherapeutic goal. For instance, excitatory-amino acid receptorexcitotoxicity has been implicated in the pathophysiology of numerousneurological disorders, including the etiology of cerebral deficitssubsequent to cardiac bypass surgery and grafting, stroke, cerebralischemia, spinal cord lesions resulting from trauma or inflammation,perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. Inaddition, excitotoxicity has been implicated in chronicneurodegenerative conditions including Alzheimer's Disease, Huntington'sChorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateralsclerosis, idiopathic and drug-induced Parkinson's Disease, as well asocular damage and retinopathy. Other neurological disorders implicatedwith excitotoxicity and/or glutamate dysfunction include muscularspasticity including tremors, drug tolerance and withdrawal, brainedema, convulsive disorders including epilepsy, depression, anxiety andanxiety related-disorders such as post-traumatic stress syndrome,tardive dyskinesia, and psychosis related to depression, schizophrenia,bipolar disorder, mania, and drug intoxication or addiction (seegenerally U.S. Pat. No. 5,446,051 and 5,670,516). Excitatory amino acidreceptor antagonists may also be useful as analgesic agents and fortreating or preventing various forms of headache, including clusterheadache, tension-type headache, and chronic daily headache. Inaddition, published International Patent application WO 98/45720 reportsthat excitatory amino acid receptor excitotoxicity participates in theetiology of acute and chronic pain states including severe pain,intractable pain, neuropathic pain, post-traumatic pain.

It is also known that trigeminal ganglia, and their associated nervepathways, are associated with painful sensations of the head and facesuch as headache and, in particular, migraine. Moskowitz (Cephalalgia,12, 5-7, (1992) proposed that unknown triggers stimulate the trigeminalganglia which in turn innervate vasculature within cephalic tissue,giving rise to the release of vasoactive neuropeptides from axonsinnervating the vasculature. These neuropeptides initiate a series ofevents leading to neurogenic inflammation of the meninges, a consequenceof which is pain. This neurogenic inflammation is blocked by sumatriptanat doses similar to those required to treat acute migraine in humans.However, such doses of sumatriptan are associated with contraindicationsas a result of sumatriptan's attendant vasoconstrictive properties.(seeMacIntyre, P. D., et al., British Journal of Clinical Pharmacology, 34,541-546 (1992); Chester, A. H., et al., Cardiovascular Research, 24,932-937 (1990); Conner, H. E., et al., European Journal of Pharmacology,161, 91-94 (1990)). Recently, it has been reported that all five membersof the kainate subtype of ionotropic glutamate receptors are expressedon rat trigeminal ganglion neurons, and in particular, high levels ofGluR₅ and KA2 have been observed. (Sahara et al., The Journal ofNeuroscience, 17(17), 6611 (1997)). As such, migraine presents yetanother neurological disorder which may be implicated with glutamatereceptor excitotoxicity.

The use of a neuroprotective agent, such as an excitatory amino acidreceptor antagonist, is believed to be useful in treating or preventingall of the aforementioned disorders and/or reducing the amount ofneurological damage associated with these disorders. For example,studies have shown that AMPA receptor antagonists are neuroprotective infocal and global ischemia models. The competitive AMPA receptorantagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline)has been reported effective in preventing global and focal ischemicdamage. Sheardown et al., Science, 247, 571 (1900); Buchan et al.,Neuroreport, 2, 473 (1991); LaPeillet et al., Brain Research, 571, 115(1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has beenshown to be an effective neuroprotective agent in rat global ischemiamodels. LaPeillet et al., Brain Research, 571, 115 (1992). EuropeanPatent Application Publication No. 590789A1 and U.S. Pat. Nos. 5,446,051and 5,670,516 disclose that certain decahydroisoquinoline derivativecompounds are AMPA receptor antagonists and, as such, are useful in thetreatment of a multitude of disorders conditions, including pain andmigraine headache. WO 98/45270 discloses that certaindecahydroisoquinoline derivative compounds are selective antagonists ofthe iGluR₅ receptor and are useful for the treatment of various types ofpain, including; severe, chronic, intractable, and neuropathic pain.

In accordance with the present invention, Applicants have discoverednovel compounds that are antagonists of the iGluR₅ receptor subtype and,thus, could be useful in treating the multitude of neurologicaldisorders or neurodegenerative diseases, as discussed above. Suchantagonists could address a long felt need for safe and effectivetreatments for neruological disorders, without attending side effects.The treatment of neurological disorders and neurodegenerative diseasesis hereby furthered.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I

wherein

Z represents a sulfur or oxygen atom;

R¹ represents hydrogen, CN, (C₁-C₄)alkyl-CO₂H, CO₂H, or tetrazole;

R² represents hydrogen, halo, aryl, substituted aryl, CO₂H, tetrazole,(C₁-C₄)alkyl, (C₁-C₄)alkylaryl, heterocycle, substituted heterocycle,CF₃, NHR³, or O—R⁴;

R³ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkylaryl, or aryl;

R⁴ represents (C₁-C₆)alkyl, (C₁-C₄)alkylaryl, (C₁-C₄)alkyl-heterocycle,(C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₃-C₁₀)cycloalkyl,(C₁-C₄)alkyl(substituted)aryl, aryl, or heterocycle; and

W, X, and Y each independently represent hydrogen, halo, (C₁-C₆)alkyl,(C₁-C₄)alkoxy, aryl, substituted aryl, CO₂H, CO(NH₂), CF₃, NH-aryl, NH₂,or NO₂, or optionally, X and R² together, or W and X together, or Y andR² together, along with the carbon atoms to which they are attached,form a benzo-fused group;

with the proviso that where Z is sulfur, then R¹ is hydrogen, CO₂H, ortetrazole, R² is hydrogen, Halo, (C₁-C₄)alkyl, or CO₂H, and W, X, and Yare each hydrogen, Halo, (C₁-C₆)alkyl, CO₂H, or CO(NH₂);

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the present invention provides a method oftreating or preventing a neurological disorder, or neurodegenerativecondition, comprising administering to a patient in need thereof aneffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt or prodrug thereof. Examples of such neurologicaldisorders, or neurodegenerative conditions, include: cerebral deficitssubsequent to cardiac bypass surgery and grafting; stroke; cerebralischemia; spinal cord lesions resulting from trauma or inflammation;perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage;Alzheimer's Disease; Huntington's Chorea; inherited ataxias;AIDS-induced dementia; amyotrophic lateral sclerosis; idiopathic anddrug-induced Parkinson's Disease; ocular damage and retinopathy;muscular spasticity including tremors; drug tolerance and withdrawal;brain edema; convulsive disorders including epilepsy; depression;anxiety and anxiety related disorders such as post-traumatic stresssyndrome; tardive dyskinesia; psychosis related to depression,schizophrenia, bipolar disorder, mania, and drug intoxication oraddiction; headache, including cluster headache, tension-type headache,and chronic daily headache; migraine; and acute and chronic pain statesincluding severe pain, intractable pain, neuropathic pain, andpost-traumatic pain.

More specifically, the present invention provides a method of treatingor preventing pain or migraine comprising administering to a patient inneed thereof an effective amount of a compound of Formula I, or apharmaceutically acceptable salt or prodrug thereof.

In addition, the present invention provides pharmaceutical compositionsof compounds of Formula I, including the pharmaceutically acceptablesalts, prodrugs, and hydrates thereof, comprising, a compound of FormulaI in combination with a pharmaceutically acceptable carrier, diluent orexcipient. This invention also encompasses novel intermediates, andprocesses for the synthesis of the compounds of Formula I.

Specifically, The present invention also provides a process for makingcompounds of Formula I(a):

wherein,

-   -   Z represents oxygen    -   R⁵, R⁸′, and R¹⁰ each independently represents hydrogen,        (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,        (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆        dialkylamine, (C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine,        or (C₁-C₆)alkyl-morpholine; with the proviso that where R⁷ is        CO₂R¹⁰; or W′, X′, or Y′ is CO₂ R⁸, then at least one, but no        more than two of R⁵, R⁸, and R¹⁰ is other than hydrogen;    -   R⁶ represents tetrazole;    -   R⁷ represents hydrogen, halo, aryl, substituted aryl, CO₂R¹⁰,        tetrazole, (C₁-C₄)alkyl, (C₁-C₄)alklaryl, heterocycle,        substituted heterocycle, CF₃, NHR³, or OR⁴;    -   R³ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alklaryl, or aryl;    -   R⁴ represents (C₁-C₆)alkyl, (C₁-C₄)alkylaryl,        (C₁-C₄)alkyl-heterocycle, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl, (C₁-C₄)alkyl(substituted)aryl, aryl, or        heterocycle; and    -   W′, X′ and Y′ each independently represent hydrogen, halo,        (C₁-C₆)alkyl, CO₂R⁸, or CO(NH₂); or optionally, X′ and R⁷        together, or W′ and X′ together, or Y′ and R⁷ together, along        with the carbon atoms to which they are attached, form a        benzo-fused group;        comprising combining a compound of structure (10):

wherein Pg is a suitable nitrogen protecting group,with a suitable base in a suitable solvent followed by addition of acompound of structure (11b):

wherein Pg is a suitable nitrogen protecting group;

-   -   R² represents hydrogen, halo, aryl, substituted aryl, CO₂H,        tetrazole, (C₁-C₄)alkyl, (C₁-C₄)alkylaryl, heterocycle,        substituted heterocycle, CF₃, NHR³, or OR⁴;    -   R³ and R⁴ are as defined above, and    -   W, X, and Y each independently represent hydrogen, halo,        (C₁-C₆)alkyl, (C₁-C₄)alkoxy, aryl, substituted aryl, CO₂H,        CO(NH₂), CF₃, NH-aryl, NH₂, or NO₂, or optionally, X and R²        together, or W and X together, or Y and R² together, along with        the carbon atoms to which they are attached, form a benzo-fused        group;        followed by esterification to a compound of structure (12b)

wherein Pg, R⁵, R⁷, W′, X′, and Y′ are as defined above;

followed by removal of the nitrogen protecting groups, and precipitationwith a suitable acid.

In a further embodiment, the present invention provides yet anotherprocess for synthesizing a compound of Formula I(a):

wherein,

-   -   Z represents oxygen;    -   R⁵, R⁸, and R¹⁰ each independently represents hydrogen,        (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,        (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆        dialkylamine, (C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine,        or (C₁-C₆)allyl-morpholine; with the proviso that where R⁷ is        CO₂R¹⁰; or W′, X′, or Y′ is CO₂ R⁸, then at least one, but no        more than two of R⁵, R⁸, and R¹⁰ is other than hydrogen;    -   R⁶ represents tetrazole;    -   R⁷ represents hydrogen, halo, aryl, substituted aryl, Co₂R¹⁰,        tetrazole, (C₁-C₄)alkyl, (C₁-C₄)alkylaryl, heterocycle,        substituted heterocycle, CF₃, NHR³, or OR⁴;    -   R³ represents hydrogen, (C₁-C₄)alkyl, (C₁-C₄)alkylaryl, or aryl,    -   R⁴ represents (C₁-C₆)alkyl, (C₁-C₄)alkylaryl,        (C₁-C₄)alkyl-heterocycle, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,        (C₃-C₁₀)cycloalkyl, (C₁-C₄)alkyl(substituted)aryl, aryl, or        heterocycle; and    -   W′, X′ and Y′ each independently represent hydrogen, halo,        (C₁-C₆)alkyl, CO₂R⁸, or CO(NH₂); or optionally, X′ and R⁷        together, or W′ and X′ together, or Y′ and R⁷ together, along        with the carbon atoms to which they are attached, form a        benzo-fused group;        comprising combining a compound of structure (10):

wherein Pg is a suitable nitrogen protecting group,with a suitable base in a suitable solvent, followed by addition of acompound of structure (11a):

wherein,

-   -   R² represents hydrogen, halo, aryl, substituted aryl, CO₂H,        tetrazole, (C₁-C₄)alkyl, (C₁-C₄)alkylaryl, heterocycle,        substituted heterocycle, CF₃, NHR³, or OR⁴;    -   R³ and R⁴ are as defined above, and    -   W, X, and Y each independently represent hydrogen, halo,        (C₁-C₆)alkyl, (C₁-C₄)alkoxy, aryl, substituted aryl, CO₂H,        CO(NH₂), CF₃, NH-aryl, NH₂, or NO₂, or optionally, X and R²        together, or W and X together, or Y and R² together, along with        the carbon atoms to which they are attached, form a benzo-fused        group;        followed by deprotection of the nitrogen group, precipitation        with a suitable acid, and crystallization of the hydrate salt of        structure (12e):

wherein R2, W, X, and Y are as defined above;

followed by treatment with a suitable alcohol in the presence suitableacid to effect the one step esterification and crystallization ofFormula I(a).

The present invention also provides the use of a compound of Formula Iof Formula I(a) for the manufacture of a medicament for treating orpreventing a neurological disorder, or neurodegenerative condition.

More specifically, the present invention provides the use of a compoundof Formula I or Formula I(a) for the manufacture of a medicament fortreating or preventing pain or migraine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds functional as iGluR₅ receptorantagonists as well as pharmaceutically acceptable salts, prodrugs, andcompositions thereof. These compounds are useful in treating orpreventing neurological disorders, or neurodegenerative diseases,particularly pain and migraine. As such, methods for the treatment orprevention of neurological disorders, or neurodegenerative diseases, arealso provided by the present invention.

In addition, it should be understood by the skilled artisan that all ofthe compounds useful for the methods of the present invention areavailable for prodrug formulation. As used herein, the term “prodrug”refers to a compound of Formula I which has been structurally modifiedsuch that in vivo the prodrug is converted, for example, by hydrolytic,oxidative, reductive, or enzymatic cleavage into the parent compound(e.g. the carboxylic acid (drug), or as the case may be the parentdicarboxylic acid (drug)) as given by Formula I. Such prodrugs may be,for example, metabolically labile mono- or di-ester derivatives of theparent compounds having a carboxylic acid group(s). It is to beunderstood that the present invention includes any such prodrugs, suchas metabolically labile ester or diester derivatives of compounds of theFormula. In all cases, the use of the compounds described herein asprodrugs is contemplated, and often is preferred, and thus, the prodrugsof all of the compounds provided are encompassed in the names of thecompounds herein. Conventional procedures for the selection andpreparation of suitable prodrugs are well known to one of ordinary skillin the art.

More specifically, examples of prodrugs of Formula I which areunderstood to be included within the scope of the present invention, arerepresented by Formulas Ia below:

wherein

Z is as defined hereinabove;

R⁵ represents hydrogen, (C₁-C₂₀)alkyl, (C₂-C₆)alkenyl, (C₁-C₆)alkylaryl,(C₁-C₆)alkyl(C₃-C₁₀)Cycloalkyl, (C₁-C₆)alkyl-N,N—C₁-C₆ dialkylamine,(C₁-C₆)alkyl-pyrrolidine, (C₁-C₆)alkyl-piperidine, or(C₁-C₆)alkyl-morpholine;

R⁶ represents hydrogen, CN, (C₁-C₄)alkyl-CO₂R⁹, CO₂R⁹, or tetrazole;

R⁷ represents hydrogen, halo, aryl, substituted aryl, CO₂R¹⁰, tetrazole,(C₁-C₄)alkyl, (C₁-C₄)alkylaryl, heterocycle, substituted heterocycle,CF₃, NHR³, or O—R⁴;

R³ and R⁴ are as defined hereinabove;

W′, X′ and Y′ each independently represent hydrogen, halo, (C₁-C₆)alkyl,CO₂R⁸, or CO(NH₂); or optionally, X′ and R⁷ together, or W′ and X′together, or Y′ and R⁷ together, along with the carbon atoms to whichthey are attached, form a benzo-fused group;

with the proviso that where Z is sulfur, then R⁶ is hydrogen, CO₂R⁹ ortetrazole, R⁷ is hydrogen, Halo, (C₁-C₄)alkyl, or CO₂R¹⁰, and W′, X′,and Y′ are each independently hydrogen, Halo, (C₁-C₆)alkyl, CO₂R⁹ orCO(NH₂);

R⁸, R⁹, and R¹⁰ each independently represent hydrogen, (C₁-C₂₀)alkyl,(C₂-C₆)alkenyl, (C₁-C₆)alkylaryl, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkyl-NN—C₁-C₆ dialkylamine, (C₁-C₆)alkyl-pyrrolidine,(C₁-C₆)alkyl-piperidine, or (C₁-C₆)alkyl-morpholine;

with the further proviso that where R⁶ is (C₁-C₄)alkyl-CO₂R⁹ or Co₂R⁹;or R⁷ is CO₂R¹⁰; or W′, X′, or Y′ is CO₂ R⁸, then at least one, but nomore than two of R⁵, R⁸, R⁹, and R¹⁰ is other than hydrogen;

or a pharmaceutically acceptable salt thereof.

It is understood that the iGluR₅ receptor antagonists of the presentinvention may exist as pharmaceutically acceptable salts and, as such,salts are therefore included within the scope of the present invention.The term “pharmaceutically acceptable salt” as used herein, refers tosalts of the compounds provided by, or employed in the present inventionwhich are substantially non-toxic to living organisms. Typicalpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with apharmaceutically acceptable mineral or organic acid or an organic orinorganic base. Such salts are known as acid addition and base additionsalts.

It will be understood by the skilled reader that most or all of thecompounds used in the present invention are capable of forming salts,and that the salt forms of pharmaceuticals are commonly used, oftenbecause they are more readily crystallized and purified than are thefree bases. In all cases, the use of the pharmaceuticals describedherein as salts is contemplated in the description herein, and often ispreferred, and the pharmaceutically acceptable salts of all of thecompounds are included in the names of them.

Acids commonly employed to form acid addition salts are inorganic acidssuch as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, and the like, and organic acids such asp-toluenesulfonic, methanesulfonic acid, oxalic acid,p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of suchpharmaceutically acceptable salts are the sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide,hydroiodide, dihydroiodide, acetate, propionate, decanoate, caprylate,acrylate, formate, hydrochloride, dihydrochloride, isobutyrate,caproate, heptanoate, propiolate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,α-hydroxybutyrate, glycolate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate,mandelate and the like. Preferred pharmaceutically acceptable acidaddition salts are those formed with mineral acids such as hydrochloricacid and hydrobromic acid, and those formed with organic acids such asmaleic acid, mandelic acid, p-toluenesulfonic acid, and methanesulfonicacid.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, sodium carbonate, sodiumbicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like. The potassium and sodium salt forms areparticularly preferred. It should be recognized that the particularcounterion forming a part of any salt of this invention is usually notof a critical nature, so long as the salt as a whole ispharmacologically acceptable and as long as the counterion does notcontribute undesired qualities to the salt as a whole. It is furtherunderstood that such salts may exist as a hydrate.

As used herein, the term “stereoisomer” refers to a compound made up ofthe same atoms bonded by the same bonds but having differentthree-dimensional structures which are not interchangeable. Thethree-dimensional structures are called configurations. As used herein,the term “enantiomer” refers to two stereoisomers whose molecules arenonsuperimposable mirror images of one another. The term “chiral center”refers to a carbon atom to which four different groups are attached. Asused herein, the term “diastereomers” refers to stereoisomers which arenot enantiomers. In addition, two diastereomers which have a differentconfiguration at only one chiral center are referred to herein as“epimers”. The terms “racemate”, “racemic mixture” or “racemicmodification” refer to a mixture of equal parts of enantiomers.

The term “enantiomeric enrichment” as used herein refers to the increasein the amount of one enantiomer as compared to the other. A convenientmethod of expressing the enantiomeric enrichment achieved is the conceptof enantiomeric excess, or “ee”, which is found using the followingequation: ${ee} = {\frac{E^{1} - E^{2}}{E^{1} + E^{2}} \times 100}$wherein E¹ is the amount of the first enantiomer and E² is the amount ofthe second enantiomer. Thus, if the initial ratio of the two enantiomersis 50:50, such as is present in a racemic mixture, and an enantiomericenrichment sufficient to produce a final ratio of 50:30 is achieved, theee with respect to the first enantiomer is 25%. However, if the finalratio is 90:10, the ee with respect to the first enantiomer is 80%. Anee of greater than 90% is preferred, an ee of greater than 95% is mostpreferred and an ee of greater than 99% is most especially preferred.Enantiomeric enrichment is readily determined by one of ordinary skillin the art using standard techniques and procedures, such as gas or highperformance liquid chromatography with a chiral column. Choice of theappropriate chiral column, eluent and conditions necessary to effectseparation of the enantiomeric pair is well within the knowledge of oneof ordinary skill in the art. In addition, the enantiomers of compoundsof Formula I can be resolved by one of ordinary skill in the art usingstandard techniques well known in the art, such as those described by J.Jacques, et al., “Enantiomers, Racemates, and Resolutions”, John Wileyand Sons, Inc., 1981.

The compounds of the present invention have one or more chiral centersand may exist in a variety of stereoisomeric configurations. As aconsequence of these chiral centers, the compounds of the presentinvention occur as racemates, mixtures of enantiomers and as individualenantiomers, as well as diastereomers and mixtures of diastereomers. Allsuch racemates, enantiomers, and diastereomers are within the scope ofthe present invention.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). A partial list of priorities and a discussionof stereochemistry is contained in “Nomenclature of Organic Compounds:Principles and Practice”, (J. H. Fletcher, et al., eds., 1974) at pages103-120.

The specific stereoisomers and enantiomers of compounds of Formula I canbe prepared by one of ordinary skill in the art utilizing well knowntechniques and processes, such as those disclosed by Eliel and Wilen,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994,Chapter 7, Separation of Stereoisomers. Resolution.

Racemization, and by Collet and Wilen, “Enantiomers, Racemates, andResolutions”, John Wiley & Sons, Inc., 1981. For example, the specificstereoisomers and enantiomers can be prepared by stereospecificsyntheses using enantiomerically and geometrically pure, orenantiomerically or geometrically enriched starting materials. Inaddition, the specific stereoisomers and enantiomers can be resolved andrecovered by techniques such as chromatography on chiral stationaryphases, enzymatic resolution or fractional recrystallization of additionsalts formed by reagents used for that purpose.

As used herein the term “Pg” refers to a suitable nitrogen protectinggroup. Examples of a suitable nitrogen protecting group as used hereinrefers to those groups intended to protect or block the nitrogen groupagainst undesirable reactions-during synthetic procedures. Choice of thesuitable nitrogen protecting group used will depend upon the conditionsthat will be employed in subsequent reaction steps wherein protection isrequired, and is well within the knowledge of one of ordinary skill inthe art. Commonly used nitrogen protecting groups are disclosed inGreene, “Protective Groups In Organic Synthesis,” (John Wiley & Sons,New York (1981)). Suitable nitrogen protecting groups comprise acylgroups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,phthalyl, o-nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl,4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonylgroups such as benzenesulfonyl, p-toluenesulfonyl and the like;carbamate forming groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl,benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl,isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl andthe like; and silyl groups such as trimethylsilyl and the like.Preferred suitable nitrogen protecting groups are formyl, acetyl,methyoxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl,benzyl, t-butyoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

As used herein the term “(C₁-C₄)alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 4 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl and the like.

As used herein the term “(C₁-C₆)alkyl” refers to a straight or branched,monovalent, saturated aliphatic chain of 1 to 6 carbon atoms andincludes, but is not limited to methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.

As used herein the term “(C₁-C₁₀)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 10 carbon atomsand includes, but is not limited to methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl,2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,octyl, 4-methyl-3-heptyl and the like.

As used herein the term “(C₁-C₂₀)alkyl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 20 carbon atomsand includes, but is not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl,2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-nonadecyl, n-eicosyl and the like. It is understood that the terms“(C₁-C₄)alkyl”, “(C₁-C₆)alkyl”, and “(C₁-C₁₀)alkyl” are included withinthe definition of “(C₁-C₂₀)alkyl”.

As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu”, “iBu”, and“t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, andtert-butyl respectively.

As used herein, the term “(C₁-C₄)alkoxy” refers to an oxygen atombearing a straight or branched, monovalent, saturated aliphatic chain of1 to 4 carbon atoms and includes, but is not limited to methyoxy,ethyoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

As used herein the term “(C₁-C₆)alkoxy” refers to an oxygen atom bearinga straight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms and includes, but is not limited to methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, n-pentoxy, n-hexoxy, and the like.

As used herein, the term “(C₁-C₆)alkyl(C₁-C₆)alkoxy” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a (C₁-C₆)alkoxy group attached to the aliphaticchain.

As used herein, the terms “Halo”, “Halide” or “Hal” refer to a chlorine,bromine, iodine or fluorine atom, unless otherwise specified herein.

As used herein the term “(C₂-C₆)alkenyl” refers to a straight orbranched, monovalent, unsaturated aliphatic chain having from two to sixcarbon atoms. Typical C₂-C₆ alkenyl groups include ethenyl (also knownas vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl,2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, andthe like.

As used herein, the term “aryl” refers to a monovalent carbocyclic groupcontaining one or more fused or non-fused phenyl rings and includes, forexample, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and the like. The term “substituted aryl”refers to an aryl group substituted with one or two moieties chosen fromthe group consisting of halogen, hydroxy, cyano, nitro, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, (C₁-C₆)alkyl(C₃-C₁₀)cycloalkyl, (C₁-C₆)alkylaryl,(C₁-C₆)alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl,amino, aminomethyl, trifluoromethyl, or trifluoromethoxy.

As used herein, the term “(C₁-C₆)alkylaryl” refers to a straight orbranched, monovalent, saturated aliphatic chain of 1 to 6 carbon atomswhich has an aryl group attached to the aliphatic chain. Included withinthe term “C₁-C₆ alkylaryl” are the following:

and the like.

As used herein, the term “(C₁-C₄)alky(substituted)laryl” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a “substituted ary” group attached to thealiphatic chain

As used herein, the term “aryl(C₁-C₆)alkyl” refers to an aryl groupwhich has a straight or branched, monovalent, saturated aliphatic chainof 1 to 6 carbon atoms attached to the aryl group. Included within theterm “aryl(C₁-C₆)alkyl” are the following:

and the like.

As used herein the term “(C₃-C₁₀)cycloalkyl” refers to a saturatedhydrocarbon ring structure composed of one or more fused or unfusedrings containing from three to ten carbon atoms. Typical C₃-C₁₀cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.

As used herein, the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” refers to astraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has a (C₃-C₁₀)cycloalkyl attached to the aliphaticchain. Included within the term “C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl” are thefollowing:

and the like.

As used herein, the term “(C₁-C₆) alkoxycarbonyl” refers to a carbonylgroup having a (C₁-C₆)alkyl group attached to the carbonyl carbonthrough an oxygen atom. Examples of this group include t-butoxycarbonyl,methoxycarbonyl, and the like.

As used herein the term “heterocycle” refers to a five- or six-memberedring, which contains one to four heteroatoms selected from the groupconsisting of oxygen, sulfur, and nitrogen. The remaining atoms of thering are recognized as carbon by those of skill in the art. Rings may besaturated or unsaturated. Examples of heterocycle groups includethiophenyl, furyl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl,thiazolidinyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl,thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl,pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl,tetrahydropyrimdyl, pyrrolidinyl, piperidinyl, piperazinyl,pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl,thiomorpholinyl, and the like. The term “substituted heterocycle”represents a heterocycle group substituted with one or two moietieschosen from the group consisting of halogen, hydroxy, cyano, nitro, oxo,(C₁-C₆)alkyl, (C₁-C₄)alkoxy, C₁-C₆ alkyl(C₃-C₁₀)cycloalkyl,(C₁-C₆)alkylaryl, (C₁-C₆)alkoxycarbonyl, protected carboxy,carboxymethyl, hydroxymethyl, amino, aminomethyl, trifluoromethyl, ortrifluoromethoxy. Further, the heterocycle group can be optionally fusedto one or two aryl groups to form a benzo-fused group. Examples ofsubstituted heterocycle include 1,2,3,4-tetrahydrodibenzeofuranyl,2-methylbezylfuranyl, and 3,5 dimethylisoxazolyl, and the like.

As used herein, the term “benzo-fused group” refers to a phenyl groupfused to an aromatic radical or a heterocycle group. Included within theterm “benzo-fused group” are the following:

and the like, wherein all substituents are as previously definedhereinabove.

As used herein, the term “triazole-fused group” refers to a triazolegroup fused to an aromatic radical or a heterocycle group. Includedwithin the term “triazole-fused group” are the following:

and the like, wherein all substituents are as previously defined.

As used herein the term “N,N—C₁-C₆ dialkylamine” refers to a nitrogenatom substituted with two straight or branched, monovalent, saturatedaliphatic chains of 1 to 6 carbon atoms. Included within the term“N,N—C₁-C₆ dialkylamine” are —N(CH₃)₂, —N(CH₂CH₃)₂, —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₂CH₃)₂, and the like.

As used herein the term “C₁-C₆alkyl-N,N—C₁-C₆dialkylamine” refers tostraight or branched, monovalent, saturated aliphatic chain of 1 to 6carbon atoms which has an N,N—C₁-C₆ dialkylamine attached to thealiphatic chain. Included within the term “C₁-C₆ alkyl-N,N—C₁-C₆dialkylamine” are the following:

and the like.

As used herein the term “(C₁-C₆)alkyl-pyrrolidine” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has a pyrrolidine attached to the aliphatic chain. Includedwithin the scope of the term “(C₁-C₆)alkyl-pyrrolidine” are thefollowing:

and the like.

As used herein the term “(C₁-C₆)alkyl-piperidine” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has a piperidine attached to the aliphatic chain. Includedwithin the scope of the term “(C₁-C₆)alkyl-piperidine” are thefollowing:

and the like.

As used herein the term “(C₁-C₆)alkyl-morpholine” refers to a straightor branched, monovalent, saturated aliphatic chain of 1 to 6 carbonatoms which has a morpholine attached to the aliphatic chain. Includedwithin the scope of the term “C₁-C₆ alkyl-morpholine” are the following:

and the like.

The designation “

” refers to a bond that protrudes forward out of the plane of the page:

The designation “

” refers to a bond that protrudes backward out of the plane of the page.

As used herein the term “iGluR₅” refers to the kainate ionotropicglutamate receptor, subtype 5, of the larger class of excitatory aminoacid receptors.

As used herein the term “migraine” refers a disorder of the nervoussystem characterized by recurrent attacks of head pain (which are notcaused by a structural brain abnormalitiy such as those resulting fromtumor or stroke), gasrointestinal disturbances, and possiblyneurological symptoms such as visual distortion. Characteristicheadaches of migraine usually last one day and are commonly accompaniedby nausea, emesis, and photophobia.

Migraine may represent a “chronic” condition, or an “acute” episode. Theterm “chronic”, as used herein, means a condition of slow progress andlong continuance. As such, a chronic condition is treated when it isdiagnosed and treatment continued throughout the course of the disease.Conversely, the term “acute”means an exacerbated event or attack, ofshort course, followed by a period of remission. Thus, the treatment ofmigraine contemplates both acute events and chronic conditions. In anacute event, compound is administered at the onset of symptoms anddiscontinued when the symptoms disappear. As described above, a chroniccondition is treated throughout the course of the disease.

As used herein the term “patient” refers to a mammal, such a mouse,gerbil, guinea pig, rat, dog or human. It is understood, however, thatthe preferred patient is a human.

The term “iGluR₅ receptor antagonist” or “iGluR₅ antagonist”, as usedherein, refers to those excitatory amino acid receptor antagonists whichbind to, and antagonize the activity of, the iGluR₅ kainate receptorsubtype. As a preferred embodiment, the present invention furtherprovides selective iGluR₅ receptor antagonists. “Selective iGluR₅receptor antagonist” or “selective iGluR₅ antagonist” as used herein,includes those excitatory amino acid receptor antagonists whichselectively bind to, and antagonize, the iGluR₅ kainate receptorsubtype, relative to the iGluR₂ AMPA receptor subtype. Preferably, the“selective iGluR₅ antagonists” for use according to the methods of thepresent invention have a binding affinity at least 10 fold greater foriGluR₅ than for iGluR₂, more preferably at least 100 fold greater. WO98/45270 provides examples of selective iGluR₅ receptor antagonists anddiscloses methods for synthesis.

As used herein, the terms “treating”, “treatment”, or “to treat” eachmean to alleviate symptoms, eliminate the causation of resultantsymptoms either on a temporary or permanent basis, and to prevent, slowthe appearance, or reverse the progression or severity of resultantsymptoms of the named disorder. As such, the methods of this inventionencompass both therapeutic and prophylactic administration.

As used herein the term “effective amount” refers to the amount or doseof the compound, upon single or multiple dose administration to thepatient, which provides the desired effect in the patient underdiagnosis or treatment. An effective amount can be readily determined bythe attending diagnostician, as one skilled in the art, by the use ofknown techniques and by observing results obtained under analogouscircumstances. In determining the effective amount or dose of compoundadministered, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the degree of involvement or the severityof the disease involved; the response of the individual patient; theparticular compound administered; the mode of administration; thebioavailability characteristics of the preparation administered; thedose regimen selected; the use of concomitant medication; and otherrelevant circumstances.

A typical daily dose will contain from about 0.01 mg/kg to about 100mg/kg of each compound used in the present method of treatment.Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, morepreferably from about 0.1 mg/kg to about 25 mg/kg.

Oral administration is a preferred route of administering the compoundsemployed in the present invention whether administered alone, or as acombination of compounds capable of acting as an iGluR₅ receptorantagonist. Oral administration, however, is not the only route, noreven the only preferred route. Other preferred routes of administrationinclude transdermal, percutaneous, pulmonary, intravenous,intramuscular, intranasal, buccal, or intrarectal routes. Where theiGluR₅ receptor antagonist is administered as a combination ofcompounds, one of the compounds may be administered by one route, suchas oral, and the other may be administered by the transdermal,percutaneous, pulmonary, intravenous, intramuscular, intranasal, buccal,or intrarectal route, as particular circumstances require. The route ofadministration may be varied in any way, limited by the physicalproperties of the compounds and the convenience of the patient and thecaregiver.

The compounds employed in the present invention may be administered aspharmaceutical compositions and, therefore, pharmaceutical compositionsincorporating compounds of Formula I are important embodiments of thepresent invention. Such compositions may take any physical form that ispharmaceutically acceptable, but orally administered pharmaceuticalcompositions are particularly preferred. Such pharmaceuticalcompositions contain, as an active ingredient, an effective amount of acompound of Formula I, including the pharmaceutically acceptable salts,prodrugs, and hydrates thereof, which effective amount is related to thedaily dose of the compound to be administered. Each dosage unit maycontain the daily dose of a given compound, or may contain a fraction ofthe daily dose, such as one-half or one-third of the dose. The amount ofeach compound to be contained in each dosage unit depends on theidentity of the particular compound chosen for the therapy, and otherfactors such as the indication for which it is given. The pharmaceuticalcompositions of the present invention may be formulated so as to providequick, sustained, or delayed release of the active ingredient afteradministration to the patient by employing well known procedures.

Compositions are preferably formulated in a unit dosage form, eachdosage containing from about 1 to about 500 mg of each compoundindividually or in a single unit dosage form, more preferably about 5 toabout 300 mg (for example 25 mg). The term “unit dosage form” refers toa physically discrete unit suitable as unitary dosages for a patient,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical carrier, diluent, or excipient.

The inert ingredients and manner of formulation of the pharmaceuticalcompositions are conventional. The usual methods of formulation used inpharmaceutical science may be used here. All of the usual types ofcompositions may be used, including tablets, chewable tablets, capsules,solutions, parenteral solutions, intranasal sprays or powders, troches,suppositories, transdermal patches and suspensions. In general,compositions contain from about 0.5% to about 50% of the compounds intotal, depending on the desired doses and the type of composition to beused. The amount of the compound, however, is best defined as the“effective amount”, that is, the amount of each compound which providesthe desired dose to the patient in need of such treatment.

The activity of the compounds employed in the present invention do notdepend on the nature of the composition, hence, the compositions arechosen and formulated solely for convenience and economy.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starches, powdered celluloseespecially crystalline and microcrystalline cellulose, sugars such asfructose, mannitol and sucrose, grain flours, and similar ediblepowders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

Tablets are often coated with sugar as a flavor and sealant. Thecompounds may also be formulated as chewable tablets, by using largeamounts of pleasant-tasting substances such as mannitol in theformulation, as is now well-established practice. Instantly dissolvingtablet-like formulations are also now frequently used to assure that thepatient consumes the dosage form, and to avoid the difficulty inswallowing solid objects that bothers some patients.

A lubricant is often necessary in a tablet formulation to prevent thetablet and punches from sticking in the die. The lubricant is chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, algins and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acid contents of the stomach. Such formulations are createdby coating a solid dosage form with a film of a polymer which isinsoluble in acid environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

When it is desired to administer the compound as a suppository, theusual bases may be used. Cocoa butter iso a traditional suppositorybase, which may be modified by addition of waxes to raise its meltingpoint slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use, also.

Transdermal patches have become popular recently. Typically theycomprise a resinous composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with innumerable poresthrough which the drugs are pumped by osmotic action.

The following table provides an illustrative list of formulationssuitable for use with the compounds employed in the present invention.The following is provided only to illustrate the invention and shouldnot be interpreted as limiting the present invention in any way.Formulation 1 Hard gelatin capsules are prepared using the followingingredients: Quantity (mg/capsule) Active Ingredient 250 Starch, dried200 Magnesium stearate  10 Total 460 mg

The above ingredients are mixed and filled into hard gelatin capsules in460 mg quantities. Formulation 2 A tablet is prepared using theingredients below: Quantity (mg/tablet) Active Ingredient 250 Cellulose,microcrystalline 400 Silicon dioxide, fumed  10 Stearic acid  5 Total665 mg

The components are blended and compressed to form tablets each weighing665 mg. Formulation 3 An aerosol solution is prepared containing thefollowing components: Weight % Active Ingredient 0.25 Ethanol 29.75Propellant 22 70.00 (Chlorodifluoromethane) Total 100.00

The active compound is mixed with ethanol and the mixture added to aportion of the Propellant 22, cooled to −30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container. Formulation 4 Tablets eachcontaining 60 mg of active ingredient are made as follows: ActiveIngredient 60.0 mg  Starch 45.0 mg  Microcrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 150 mg  

The active ingredient, starch, and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders which are thenpassed through a No. 14 mesh U.S. sieve. The granules so produced aredried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate, and talc, previously passedthrough a No. 60 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 150 mg. Formulation 5 Capsules each containing 80 mg medicamentare made as follows: Active Ingredient 80 mg Starch 59 mgMicrocrystalline cellulose 59 mg Magnesium stearate  2 mg Total 200 mg 

The active ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 sieve, and filled into hard gelatincapsules in 200 mg quantities. Formulation 6 Suppositories eachcontaining 225 mg of active ingredient may be made as follows: ActiveIngredient   225 mg Saturated fatty acid glycerides 2,000 mg Total 2,225mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2 g capacity and allowed to cool.Formulation 7 Suspensions each containing 50 mg of medicament per 5 mldose are made as follows: Active Ingredient 50 mg Sodium carboxymethylcellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v.Color q.v. Purified water to total 5 ml

The medicament is passed through a No. 45 mesh U.S. sieve and mixed withthe sodium carboxymethyl cellulose and syrup to form a smooth paste. Thebenzoic acid solution, flavor and color are diluted with some of thewater and added, with stirring. Sufficient water is then added toproduce the required volume. Formulation 8 An intravenous formulationmay be prepared as follows: Active Ingredient 100 mg Mannitol 100 mg 5 NSodium hydroxide 200 ml Purified water to total  5 ml

It is understood by one of ordinary skill in the art that the proceduresas described above can also be readily applied to a method of treatingneurological disorders or neurodegenerative conditions, particularlypain and migraine, comprising administering to a patient an effectiveamount of a compound of Formula I.

Compounds of Formula I and Formula I(a) can be chemically prepared, forexample, by following the synthetic routes set forth in the Schemesbelow. However, the following discussion is not intended to be limitingto the scope of the present invention in any way. For example, thespecific synthetic steps for the routes described herein may be combinedin different ways, or with steps from different schemes, to prepare thecompounds of Formula I and Formula I(a). All substituents, unlessotherwise indicated, are as previously defined. The reagents andstarting materials are readily available to one of ordinary skill in theart. For example, certain starting materials can be prepared by one ofordinary skill in the art following procedures disclosed in U.S. Pat.No. 5,356,902 (issued Oct. 18, 1994) and U.S. Pat. No. 5,446,051 (issuedAug. 29, 1995) and U.S. Pat. No. 5,670,516 (issued Sep. 23, 1997) theentire contents, all of which, are herein incorporated by reference.Other necessary reagents and starting materials for the below proceduresmay be made by procedures which are selected from standard techniques oforganic and heterocyclic chemistry, techniques which are analogous tothe syntheses of known structurally similar compounds, and theprocedures described in the Examples, including novel procedures.

Compounds of Formula I, wherein Z represents an oxygen atom, may besynthesized according to Scheme I.

In Scheme I, step A, the compound of structure (1) is treated with atrialkylsilyl iodide (Alk₃SiI) and the resulting amine, withoutisolation, is protected under standard conditions to provide thecompound of structure (2). For example, when a protecting group otherthan methoxycarbonyl is desired, a solution ofethyl-6-oxo-2-methoxycarbonyl-decahydroisoquinolie-3-carboxylate,dissolved in a suitable organic solvent such as dichloromethane at roomtemperature, is treated with about 4 equivalents of a compound offormula Alk₃SiI such as trimethylsilyl iodide, triethylsilyl iodide,tributylsilyl iodide, and the like, with trimethylsilyl iodide beingmost preferred. The reaction mixture is stirred for about 10 to 20hours, quenched with ethanol and concentrated under vacuum. Theresulting solid, for example, is then dissolved in a suitable organicsolvent such as dichloromethane and treated with an excess of a suitableorganic base, such as triethylamine, followed by about 1 equivalent of,for example, di-tert-butyl dicarbonate. The reaction mixture is stirredat room temperature for 10 to 20 hours. The compound (2) is thenisolated using standard procedures. For example, the reaction mixture isconcentrated under vacuum, suspended in ethyl acetate and filtered. Thefiltrate is washed with diluted hydrochloric acid and water, the organiclayer separated and dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide concentrated compound (2). Columnchromatography may then be performed on silica gel with a suitableeluent such as 25% ethyl acetate/hexane to provide the purified compound(2). Note, where the desired protecting group (Pg) is methoxycarbonyl,the compound of structure (1) may be used directly in Step B below.

In Scheme I, Step B, compound (2) is reduced under standard conditionswith a suitable reducing reagent in the presence of a suitable Lewisacid catalyst, to provide the compound of structure (3). For example,ethyl 6-oxo-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate(compound (2) of Step A above) is mixed with about 1 equivalent of aLewis acid catalyst, such as cerium trichloride, in a suitable organicsolvent such as ethanol. The resulting solution is cooled to −78° C. andabout 1 to 2 equivalents of a reducing reagent, such as sodiumborohydride, is added and the mixture is warmed slowly to roomtemperature. After 4 to 8 hours, a suitable acid, such as acetic acid,is added at 0° C. and the resulting mixture is stirred for about 1 to 2hours at room temperature and concentrated under vacuum. The compound(3) is then isolated using standard procedures such as extractiontechniques. For example, the reaction mixture is partitioned betweenwater and an organic solvent such as ethyl acetate, and the aqueouslayer is extracted 2-4 times with ethyl acetate. The organic layers arecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to provide a mixture of compound (3) andcompound (4). Both compounds are then purified by chromatography onsilica gel with a suitable eluent such as 70% ethyl acetate/hexanes.

In Scheme I, Step C, compound (4) is treated with a compound ofstructure (5) in the presence of a phosphine and a dialkylazadicarboxylate to give the compound of structure (6). For example, asolution ofethyl-6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylate,about 1-1.5 equivalents of compound of structure (5) (wherein Urepresents hydrogen, CN, (C₁-C₄)alkyl-CO₂R⁹, or CO₂R⁹) about 0-1.5equivalents of an organic base such as pyridine, and about 1-1.5equivalents of a phosphine such as triphenylphosphine in tetrahydrofuranis treated with about 1-1.5 equivalents of a dialkyl azadicarboxylatesuch as diethyl azodicarboxylate. The reaction is then stirred at 25-70°C. for 15-48 hours. The solvents are removed under vacuum to provide thecompound of structure (6). Compound (6) is then purified bychromatography on silica gel with a suitable eluent such as diethylether/hexanes or ethyl acetate/hexanes.

In Scheme I, Step D(a), the compound of structure (6) is deprotectedunder standard conditions well known in the art to provide the compoundof structure (8). For example, compound (6) is treated with an organicsolvent such as ethyl acetate saturated with HCl at room temperature forabout 3 to 5 hours. The mixture is then concentrated under vacuum toprovide the compound of structure (8) wherein U is as defined in Step C.This material may then be purified by techniques well known in the art,such as titration with organic solvents and/or cation exchangechromatography, eluting with MeOH/water, followed by 2N ammonia in MeOH,to provide the purified compound of structure (8) wherein U is asdefined in Step C.

In Scheme I, Step D, the compound of structure (6) is hydrolyzed understandard conditions to give the compound of structure (7) wherein R¹ isother than tetrazole, but otherwise as defined hereinabove. For example,compound (6) is dissolved in a suitable organic solvent or solventsmixture, such as methanol, ethanol, tetrahydrofuran and/or ethylacetate, and treated with an excess of a suitable base. Examples ofsuitable bases include aqueous lithium hydroxide, sodium hydroxide,potassium hydroxide, and the like, with lithium hydroxide beingpreferred. The reaction is stirred for about 10-36 hours. The reactionmixture is then concentrated under vacuum, diluted with water and washedwith ethyl acetate. The aqueous layer is made acidic to pH 3-4 with 10%HCl and extracted with ethyl acetate. These organic phases are combined,dried over sodium sulfate, filtered, and concentrated under vacuum toprovide the compound (7) wherein R¹ is other than tetrazole, butotherwise as defined hereinabove. The material may then be purified bychromatography on silica gel with a suitable eluent such as ethylacetate/hexanes/acetic acid, to provide the purified compound.

In Scheme I, where it is desired that the compound of structure (7)contain a tetrazole at R¹, compound (6) (wherein U for the purposes ofthis step is nitrile) is treated with a compound of Alk₃SnN₃ in Step Eto give the compound of structure (6a). This is followed by hydroysis inStep F, to provide the compound of structure (7) (wherein R¹ istetrazole). For example, compound (6) (wherein U is nitrile) is treatedwith about 3 to 5 equivalents of azido-tri-n-butyl stannane at about 70to 100° C. for about 12 to 16 hours under an atmosphere of nitrogen togive the compound of structure (6a). Compound (6a) is then hydrolyzed,concentrated, and the resulting compound (7) (wherein R¹ is tetrazole)may then be purified, all of which occur under standard conditions wellknown in the art as described in Step D above.

As an alternative to Steps D and F above, the compounds of structure (6)and (6a) may be selectivley hydrolyzed under standard conditions knownin the art to provide a compound of structure (7a):

For example, compound (6) may be hydrolyzed to provide compounds of (7a)wherein R⁶ is as defined hereinabove, other than tetrazole, whereascompound (6a) may be hydrolyzed to provide compounds of (7a) wherein R⁶is tetrazole. Compound (7a) can then be deprotected under standardconditions to provide the compound of structure (9):

Methods for the selective hydrolysis of compounds of structure (6) and(6a) are well known in the art.

In Scheme I, Step G, the compound of structure (7) is deprotected understandard conditions well known in the art to provide the compound ofFormula I. For example, compound (7) is treated with an organic solvent,such as ethyl acetate, saturated with hydrogen chloride at roomtemperature for about 3 to 5 hours. The mixture is then concentratedunder vacuum to provide the compounds of Formula I. This material maythen be purified by techniques well known in the art, such as tritrationwith organic solvents and/or cation exchange chromatography eluting withmethanol/water, followed by 2 N ammonia in methanol, to provide thepurified compound of Formula I.

As an alternative to the sequence of Steps D and G, and as analternative to the sequence of steps F and G, the compounds of structure(6) and (6a), respectively, may be concomitantly hydrolyzed anddeprotected as provided below to provide the compounds of Formula I.

In Scheme II, compound (6) or (6a) is deprotected and hydrolyzedconcomitantly under standard conditions to provide the compounds ofFormula I. For example, in Scheme II, Step A-1, a solution of compound(6), dissolved in 6N HCl, is heated to reflux (90-950° C.) for about15-20 hours. The reaction mixture is then allowed to cool to roomtemperature and concentrated in vacuo to provide the compound of FormulaI wherein R¹ is as defined hereinabove, other than tetrazole. Thecompound of Formula I can then be purified by techniques well known inthe art, such as cation exchange chromatography eluting withmethanol/water followed by 2N ammonia in methanol or ethanol to providethe purified compound of Formula I wherein R¹ is as defined other thantetrazole. In Scheme II Step A-2, a solution of compound (6a) is treatedas described above in Step A-1 to provide the compound of Formula Iwherein R¹ is tetrazole. This material may then be purified bytechniques well known in the art, such as cation exchange chromatographyeluting with methanol/water followed by 2N ammonia in methanol orethanol to provide the purified compound of Formula I wherein R¹ istetrazole.

In Scheme I, Step H, the compound of Formula I may be nonselectively orselectively esterified to provide the compounds of Formula Ia. Forexample, the compound of Formula I is dissolved in a suitable organicsolvent, such as ethanol, isobutanol, or 2-ethylbutanol, and treatedwith an excess of a dehydrating agent such as thionyl chloride. Thereaction mixture is heated to about 120° C. for about 1 to 2 hours. Thereaction mixture is then concentrated under vacuum to provide the crudecompound of Formula Ia. This material may then be precipitated withdiethyl ether and filtered to provide the purified compound.Alternatively in Step H, the compound of Formula I can be esterified bydissolving in a suitable organic solvent such as ethanol, and treatingwith an excess of a suitable acid. Examples of suitable acids includegaseous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonicacid, and the like with gaseous hydrochloric acid being preferred. Thereaction mixture is heated to reflux (78-85° C.) for about 15-25 hours.The reaction mixture is then concentrated under vacuum to provide thecrude compound of Formula Ia. This material can then be purified bytechniques well known in the art, such as cation exchange chromatographyeluting with methanol/water followed by 2N ammonia in ethanol to providethe purified compound.

Compounds of Formula I, wherein Z represents an oxygen atom and R¹represents tetrazole may alternatively be synthesized according to theprocedures set forth in Scheme III.

In Scheme III, step A, the compound of structure (2) (as previouslydescribed in Scheme I above), is hydrolyzed to the compound of structure(9) under standard conditions well known in the art. For example, ethyl6-oxo-2-(tert-butoxycarbonyl)-decahydroisoquinoline-3-carboxylate isdissolved in a suitable organic solvent or solvents mixture, such asmethanol, ethanol, tetrahydrofuran and/or ethyl acetate, and treatedwith an excess of a suitable base. Examples of suitable bases includeaqueous lithium hydroxide, sodium hydroxide, potassium hydroxide, andthe like with lithium hydroxide being preferred. The reaction is stirredfor about 20-24 hours at room temperature. The reaction mixture is thenconcentrated under vacuum, diluted with water and washed with ethylacetate. The aqueous layer is made acidic to pH 3-4 with 10% HCl andextracted with ethyl acetate. These organic phases are combined, driedover sodium sulfate, filtered, and concentrated under vacuum to providethe compound of structure (9).

In Scheme III, Step B, compound (9) is reduced with a suitable reducingreagent, such as lithium or sodium selectride, to provide the compoundof structure (10). For example,6-oxo-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylic acid isdissolved in a suitable organic solvent such as tetrahydrofuran. Theresulting solution is cooled to about 0° C. and about 2 equivalents oflithium selectride, dissolved in tetrahydrofuran, is added. The reactionmixture is warmed slowly to room temperature. After about 2 to 3 hours,a suitable acid, such as 1N hydrochloric acid, and sodium chloride areadded and the resulting mixture is filtered. The compound (10) is thenisolated using standard procedures such as extraction techniques. Forexample, the aqueous layer is extracted 2-4 times with ethyl acetate.The organic layers are combined, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to provide the crude compound(10). Compound (10) may then be purified by chromatography on silica gelwith a suitable eluent such as 60% ethyl acetate/hexanes.

In Scheme III, Step C, compound (10) is treated with a compound ofstructure (11) in the presence of a suitable base to provide thecompound of structure (12). For example, a solution of6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylic acid,dissolved in an organic solvent such as tetrahydrofuran, is treated at0° C. with about 2-2.5 equivalents of a suitable base such as potassiumtert-butoxide. The resulting mixture is stirred at room temperature forabout 20 to 40 minutes, cooled to 0° C. and treated with about 1-1.5equivalents of compound (11) (where R², W, X, and Y are as definedhereinabove). The reaction is then stirred at room temperature for about15-24 hours. The reaction mixture is then diluted with water and washedwith ethyl acetate. The aqueous layer is made acidic to pH 3-4 with 10%HCl and extracted with ethyl acetate. These organic phases are combined,dried over sodium sulfate, filtered, and concentrated under vacuum toprovide the compound of structure (12). Compound (12) may then bepurified by chromatography on silica gel with a suitable eluent such asethyl acetate/hexanes

In Scheme II, Step p, compound (12) is treated with a compound offormula Alk₃SnN₃, wherein Alk is an alkyl group such as Me, Et, Bu, andthe like, and the resulting compound is deprotected without furthertreatment to the compound of Formula I, wherein R¹ is tetrazole, understandard conditions well known in the art. For example, compound (12) istreated with about 3 to 5 equivalents of azido tri-n-butyl stannane at70 to 100° C. for about 12 to 76 hours under an atmosphere of nitrogen.The mixture is then treated with an organic solvent, such as ethylacetate, saturated with hydrogen chloride at room temperature for about3 to 5 hours. The mixture is then concentrated under vacuum to providethe compound of Formula I, wherein R¹ is tetrazole. This material maythen be purified by techniques well known in the art, such astrituration with organic solvents and/or cation exchange chromatographyeluting with methanol/water followed by 2 N ammonia in methanol toprovide the purified compound.

In Scheme III, Step E, the compound of Formula I is nonselectively, orselectively, esterified to provide the compound of Formula Ia, whereinR⁶ is tetrazole. For example, the compound of Formula I is dissolved ina suitable base, such as ethanol, isobutanol, or 2-ethylbutanol, andtreated with an excess of a dehydrating agent, such as thionyl chloride.The reaction mixture is heated to 120° C. for about 1-2 hours. Thereaction mixture is then concentrated under vacuum to provide the crudecompound of Formula Ia, wherein R⁷ is tetrazole. This material isprecipitated with diethyl ether and filtered to provide the purifiedcompound of Formula Ia. Alternatively, in Step E, the compound ofFormula I can be esterified by dissolving in a suitable organic solventsuch as ethanol, and treating with an excess of a suitable acid.Examples of suitable acids include gaseous hydrochloric acid, aqueoussulfuric acid, p-toluene sulfonic acid, and the like with gaseoushydrochloric acid being preferred. The reaction mixture is heated toreflux (78-85° C.) for about 15-25 hours. The reaction mixture is thenconcentrated under vacuum to provide the crude compound of Formula Ia.This material can then be purified by techniques well known in the art,such as cation exchange chromatography eluting with methanol/waterfollowed by 2N ammonia in ethanol to provide the purified compound.

One of ordinary skill in the art will understand that the nitrile groupof structure (11) (see Scheme III above) can be converted to a protectedtetrazole group prior to treatment of compound (10) with compound (11)and, thus, provide yet another route of synthesis for compounds ofFormula I wherein R¹ is tetrazole. This alternate route is provided inScheme IV(a) and IV(b) below:

In Scheme IV(a), Step A, the compound of structure (11) is treated understandard conditions to provide the compound of structure (11a). Forexample, a solution of trimethyl aluminum in toluene is added to a roundbottomed flask under nitrogen and the solution cooled to about −7degrees C. Azidotrimethylsilane (about 3.86 mol) is then added viacannula such that the internal temperature of the reaction is maintainedat no greater than about 3 degrees C. To this mixture, the compound ofstructure (11) is added dropwise in a solution of toluene. The reactionis slowly warmed to RT and then heated to about 90 degrees C. Thereaction is heated at 90 degrees for about 13 hours before cooling toRT. The reaction is then cooled to about 0 degrees C. in an ice bath,then slowly transferred via cannula to a solution of 6N aqueous HCl andethyl acetate, pre-cooled to about −5 degrees C. The internaltemperature during the quench is maintained at no greater than about 5degrees. After addition, the flask is allowed to warm to roomtemperature. The reaction is then diluted with ethyl acetate to dissolveany solids, the layers are separated, and the aqueous layer extractedwith ethyl acetate. The organics are combined, washed with brine, driedover anhydrous sodium sulfate, and concentrated using standardtechniques well known in the art to provide the concentrated compound ofstructure (11a)

In Scheme IV(a), Step B, the compound of structure (11a) is protectedwith a suitable nitrogen protecting group under standard conditions toprovide the compound of structure (11b). For example, to a slurry ofcompound (11a) and 4,4′-dimethoxybezhydrol in glacial acetic acid, isadded concentrated sulfuric acid. Upon addition, the reaction becomesred and homogenous and an endotherm of about 3 to 4 degree Celsius isobserved. After about 15 minutes, the product of structure (11b) beginsto crystallize, resulting in a slight exotherm of less than about 10degrees. After about 1 hour, the product is isolated using standardtechniques, such as filtration, washed with water, and then withisopropyl alchohol. The product of compound (11b) is dried andconcentrated under vaccum to provide the concentrated compound ofstructure (11b).

In Scheme IV(b), Step A, the compound of structure (10) (from Scheme IIIabove) is treated with the compound of structure (11b) from SchemeIV(a), Step B. above, to provide the compound of structure (12a). Forexample, to a solution of sodium hydride in dry dimethyl sulfoxide, isadded compound (10) dropwise as a solution of dimethyl sulfoxide. Duringaddition, a cooling bath is used to maintain the reaction temperature ator below about 25 degrees C. The reaction is stirred for about 15minutes at ambient temperature and then compound (11b) is added in oneportion as a solid. The reaction slurry is stirred at RT for about 20minutes before heating to about 40 degrees C. for about 2.5-3 hours. Thereaction is quenched by addition of 1N aqueous HCl solution, water, andethyl acetate. The layers are separated and the aqueous layer isextracted with ethyl acetate. The combined organics are washed withwater and about a 10% solution of aqueous sodium chloride solution. Theorganic layer is then dried over anhydrous sodium sulfate andconcentrated under vaccum to provide the crude compound of structure(12a). This material may then be purified using standard techniques suchas chromatography on silica gel, eluting with a suitable eluent such as1% MeOH in methylene chloride, followed by 5% MeOH in methylene chlorideto afford the purified product of compound (12a)

As one of ordinary skill in the art will recognize, the compound ofstructure (12a) may then be deprotected using, for example TMSI(iodotrimethylsilane) in methylene chloride, to provide the compound ofFormula I, wherein R¹ is tetrazole. Alternatively, the compound ofstructure (12a) may be esterified under standard conditions well knownin the art, followed by deprotection, to provide the compound of FormulaIa, wherein R⁶ is tetrazole.

Scheme IV(a) and IV(b), above, provide procedures for the synthesis ofFormula I and I(a) compounds where R¹ or R⁶ is tetrazole, wherein theprotected hydroxy acid of compound (10) is treated with the protectedaryl tetrazole of compound 11(b) in a nucleophilic aromatic substitutionreaction to provide the compound of structure 12(a). As discussed,compound 12(a) can then be esterified and/or deprotected, all understandard conditions, to provide the compounds of Formula I(a) or FormulaI. Scheme IV(c) provides a general synthetic route for these procedures.

In Scheme IV(c), Step A, the compound of structure 12(a) is esterifiedunder standard conditions to provide the compound of structure 12(b)wherein R⁶ is tetrazole. For example, compound 12(a), dissolved in asuitable solvent such as DMF, is treated with a compound of the formulaR⁵-LG where LG represents a suitable leaving group such as a halide. Forexample R⁵ is as defined previously and LG represents a chloro or bromoatom. The reaction is heated until complete (confirmed for example byTLC and HPLC). For example, heating at 80° C. under nitrogen for about 1hour. The reaction is then cooled to ambient temperature and submittedto standard extractive worhup techniques know to the skilled artisan toprovide purified compound 12(b), wherein R⁶ is tetrazole.

In Scheme IV(c), Steps B and C, the compound of structure 12(a) or 12(b)is deprotected under standard conditions to provide Formula I or FormulaI(a) wherein R¹ or R⁶ is tetrazole. For example, to a solution ofcompound 12(a) or 12(b) is added anisole and trifluoroacetic acid (TFA).The solution is stired until the reaction is complete. For examplestirring for 6 hours at room temperature. The product, compound 12(c) or12(d), can be isolated by standard workup conditions.

Compounds 12(c) and 12(d) are further deprotected in Step C to providethe final products of Formula I or I(a) (wherein R¹ or R⁶ is tetrazole).For example, compound 12(c) or 12(d) is combined with TMSI in CH₂Cl₂ andthe reaction is stired until complete. The Final compounds of Formula Ior I(a) wherein R¹ or R⁶ is tetrazole may be isolated after standardworkup conditions.

Surprisingly, and as a further embodiment of the present invention,Applicants have discovered alternative nucleophilic aromaticsubstitution procedures for the synthesis of Formula I or Formula I(a)(wherein R¹ or R⁶ is tetrazole) that offer additional advantages overthe procedures described in Schemes IV(a)-IV(c). These additionalprocedures are generally provided in Scheme IV(d), below.

In Scheme IV(d), Step A, compound (10) is treated with an unprotectedaryl tetrazole of structure 11(a) to provide the compound of structure12(c). For example, to a solution of a suitable base, such as potassiumtert-butoxide, in a suitable solvent, such as THF, is added the compoundof structure (10) and the unprotected aryl tetrazole of structure 11(a).The reaction is heated until complete. For example, the reaction isheated to about 65° C. for about 4 hours. The compound 12(c) is isolatedby standard workup techniques.

In Scheme IV(d), Step B, compound 12(c) is deprotected to provide thecompound of Formula I wherein R¹ is tetrazole. For example, to asolution of a suitable base, such as 85% KOH in water, compound 12(c) isadded and the mixture is heated to about 100° C. until the reaction iscomplete. The mixture is cooled then added to a suitable acid, such asHCl, to provide the precipitated acid salt of Formula I, wherein R¹ istetrazole. The acid salt of Formula I (R¹ is tetrazole) can purified bystandard recrystallization techniques and isolated as the salt or asolvate thereof such as the hydrate.

In Scheme IV(d), Step C, Formula I is esterifed with a compound of theformula R⁵—OH under standard conditions. For example, a mixture of thehydrate salt of Formula I (Step B above), a suitable acid such asp-toluenesulfonic acid monohydrate, a compound of formula R⁵—OH, andwater is heated to about 140° C. until complete. The ester salt ofFormula I(a) where R6 is tetrazole is isolated by standard techniquesand may be purified by standard recrystallization techniques.

Compounds of Formula I, wherein Z represents a sulfur atom, may besynthesized according to Scheme V.

In Scheme V, step A, the compound of structure (3) is treated understandard conditions with a compound of formula Lg-Hal, wherein Lg is asuitable leaving group and Hal represents a chloro, bromo or iodo atom,to provide the compound of structure (13). For example, a solution ofethyl-6-hydroxy-2-(methoxycarbonyl)-decahydroisoquinoline-3-carboxylate,dissolved in a suitable organic solvent such as dichloromethane andcooled to 0° C., is treated with an excess of a suitable organic base,such as triethylamine, followed by about 1 to 2 equivalents of acompound of formula Lg-Hal. Examples of Lg-Hal include includem-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride,p-bromobenzenesulfonyl chloride, p-toluenesulfonyl chloride,benzenesulfonyl chloride, methanesulfonyl chloride,trifluoromethanesulfonyl chloride, and the like, with methanesulfonylchloride being a preferred compound. The reaction mixture is warmed toroom temperature and stirred for about 3 to 20 hours. The compound ofstructure (13) is then isolated using standard procedures. For example,the reaction mixture is washed with water, the organic layer separated,washed with aqueous saturated solution of ammonium chloride, and driedover anhydrous sodium sulfate, filtered, and concentrated under vacuumto provide concentrated compound (13). If desired, column chromatographymay then be performed with on silica gel with a suitable eluent such as10-50% ethyl acetate/hexane to provide the purified compound (13).

In Scheme V, Step B, compound (13) is treated with an aryl thiol ofstructure (14) to provide the compound of structure (15). For example,ethylmethanesulfonyloxy-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylateis mixed with about 1-2.5 equivalents of substituted aryl thiol (whereinU represents hydrogen, CN, (C₁-C₄)alkyl-CO₂R⁹, or CO₂R⁹ and where allother substituents are as defined hereinabove) and about 1-2.5equivalents of potassium carbonate and heated at reflux in a suitablesolvent such as acetone for about 24-48 hours. The reaction mixture iscooled to room temperature and compound (15) is then isolated usingstandard procedures such as extraction techniques. For example, thereaction mixture is partitioned between water and an organic solventsuch as ethyl acetate, and the aqueous layer extracted 24 times withethyl acetate. The organic layers are combined, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum to provideconcentrated compound (15). Compound (15) may then be purified bychromatography on silica gel with a suitable eluent such as ethylacetate/hexanes.

In Scheme V, Step C, compound (15) is concomitantly deprotected andhydrolyzed under standard conditions to provide the compound of FormulaI wherein R¹ is other than tetrazole, but otherwise as definedhereinabove. For example, a solution of compound (15) dissolved in 6MHCl is heated to reflux for about 20-50 hours. The reaction mixture isthen allowed to cool to room temperature and concentrated in vacuo toprovide the compound of Formula I wherein R¹ is other than tetrazole,but otherwise as defined hereinabove. The compound of Formula I may thenbe purified by techniques well known in the art, such as cation exchangechromatography eluting with methanol/water followed by 2 N ammonia inmethanol or ethanol to provide the purified compound.

In Scheme V, Step D, where it is desired that the compound of Formula Icontain a tetrazole at R¹, compound (15), wherein U is nitrile, istreated under standard conditions with a compound of formula Alk₃SnN₃,wherein Alk is an alkyl chain, to provide the compound of structure(16). For example, when U is a nitrile group, compound (15) is treatedwith about 2 to 5 equivalents of azido tri-n-butyl stannane at 70 to100° C. for about 72-120 hours under an atmosphere of nitrogen to givecompound (16). Purification of compound (16) may be achieved by standardflash chromatography using silical gel and a suitable eluent.

In Scheme V, Step E, compound (16) is concomitantly deprotected andhydrolyzed under standard conditions to provide the compound of FormulaI, wherein R¹ is tetrazole. For example, a solution of compound (16),dissolved in 6M HCl, is heated to reflux for about 20-50 hours. Thereaction mixture is then allowed to cool to room temperature, andconcentrated in vacuo to provide the compound of Formula I wherein R¹ istetrazole. The compound of Formula I may then be purified by techniqueswell known in the art, such as cation exchange chromatography elutingwith methanol/water, followed by 2 N ammonia in methanol or ethanol toprovide the purified compound of Formula I wherein R¹ is tetrazole.

In Scheme V, Step F, the compound of Formula I is esterified understandard conditions well known in the art to provide the compound ofFormula Ia. For example, the compound of Formula I is dissolved in asuitable organic solvent such as ethanol, and treated with an excess ofa suitable acid. Examples of suitable acids include gaseous hydrochloricacid, aqueous sulfuric acid, p-toluene sulfonic acid, and the like withgaseous hydrochloric acid being preferred. The reaction mixture isheated to reflux (78-85° C.) for about 15-24 hours. The reaction mixtureis concentrated under vacuum to provide the crude compound of FormulaIa. This material may then be purified by techniques well known in theart, such as cation exchange chromatography eluting with methanol/water,followed by 2 N ammonia in ethanol to provide the purified compound ofFormula Ia.

The Formula I compounds of the present invention may be chemicallysynthesized, for example, from a6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate, or a6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate, or a6-hydroxy-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate. These intermediates, in turn, may be synthesized from a6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid, thesynthesis of which is described in U.S. Pat. Nos. 4,902,695, 5,446,051,and 5,356,902 (the contents of which are all herein incorporated byreference). A route for the synthesis of the6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate, useful for the synthesis of the compounds of the presentinvention, is shown in Scheme VI below. Synthesis of the6-hydroxy-2-tert-butoxycarbonyl-decahydroisoquinoline-3-carboxylateintermediate is provided in Preparation 1 (infra), while synthesis ofthe 6-hydroxy-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate isprovided, for example, essentially as described in. Scheme I (Steps Aand B) and as provided in U.S. Pat. Nos. 4,902,695, 5,446,051, and5,356,902.

In Scheme VI, Step A, 6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylicacid (Pg is as herein defined above) is esterified by reaction with acompound of formula R⁵-Br (where R⁵ is as herein defined) to provide the6-oxo-2-(Pg)-decahydroisoquinoline-3-carboxylate intermediate ofcompound (2). For example6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylic acid isdissolved in acetonitrile and treated with triethylamine andbromoethane. The reaction is heated at 50° C. for about 3 hours, cooledand partitioned between 50:50 ethyl acetate/heptane and 1N HCL. Theorganic phase is isolated and washed 3 times with water, saturatedsodium bicarbonate, brine, dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to provide ethyl6-oxo-2-methoxycarbonyl-decahydroisoquinoline-3-carboxylate, a compoundof structure (2). This crude material may then be purified understandard conditions well known in the art. For example, the crudematerial is dissolved in 10% ethyl acetate/heptane and applied to a plugof silica gel (10 g in 10% ethyl acetate/heptane). The plug is elutedwith, 10% ethyl acetate/heptane, 15% ethyl acetate/heptane, and 25%ethyl acetate/heptane. The eluents are combined and concentrated undervacuum to provide the purified compound of structure (2).

The following preparations and examples further illustrate the inventionand represent typical synthesis of the compounds of Formula I asdescribed generally above. The reagents and starting materials arereadily available, to one of ordinary skill in the art. As used herein,the following terms have the meanings indicated: “i.v.” refers tointravenously; “p.o.” refers to orally; “i.p.” refers tointraperitoneally; “eq” or “equiv.” refers to equivalents; “g” refers tograms; “mg” refers to milligrams; “L” refers to liters; “mL” refers tomilliliters; “μL” refers to microliters; “mol” refers to moles; “mmol”refers to millimoles; “psi” refers to pounds per square inch; “mm Hg”refers to millimeters of mercury; “min” refers to minutes; “h” or “hr”refers to hours; “° C.” refers to degrees Celsius; “TLC” refers to thinlayer chromatography; “HPLC” refers to high performance liquidchromatography; “R_(f)” refers to retention factor; “R_(t)” refers toretention time; “δ” refers to part per million down-field fromtetramethylsilane; “THF” refers to tetrahydrofuran; “DMF” refers toN,N-dimethylformamide; “DMSO” refers to dimethyl sulfoxide; “aq” refersto aqueous; “EtOAc” refers to ethyl acetate; “iProAc” refers toisopropyl acetate; “MeOH” refers to methanol; “MTBE” refers totert-butyl methyl ether; “PPh₃” refers to triphenylphosphine; “DEAD”refers to diethyl azodicarboxylate; “RT” refers to room temperature;“K_(i)” refers to the dissociation constant of an enzyme-antagonistcomplex and serves as an index of ligand binding; and “ID₅₀” and “ID₁₀₀”refer to doses of an administered therapeutic agent which produce,respectively, a 50% and 100% reduction in a physiological response.

Preparation 1 Ethyl (3S, 4aR, 6R, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

A. Ethyl (3S, 4aR, 6R, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a −78° C. solution of (3S, 4aR, 8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (6.88 g, 21.14 mmol)(see Preparation 2, Steps A and B, below andScheme III, Step A generally) and cerium trichloride heptahydrate (7.9g, 21.2 mmol) in absolute ethyl alcohol (90 mL), under nitrogen sodiumborohydride (1.24 g, 32.73 mmol) was added in portions. The resultingmixture was slowly warmed up to room temperature over 5 hours. Thereaction mixture was cooled down to 0° C. and acetic acid (50% in water,25 mL) was carefully added. The resulting mixture was stirred for 1 hourat room temperature and the solvent was removed in vacuo. To theresulting material water and ethyl acetate were added and the phasesseparated. Aqueous layer was extracted with ethyl acetate (3×). Thecombined organic phases were dried, filtered and concentrated in vacuo.Flash chromatography (silicagel, 70% ethyl acetate/hexane) gave ethyl(3S, 4aR, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate(2.4 g, 35%) and the title compound (4.15 g, 60%)

Ion Electrospray Mass Spectrum M+Na: 350.2

EXAMPLE 1 Preparation of (3S, 4aR, 6S, 8aR)6-(3-Carboxy-naphthalen-2-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(3-ethoxycarbonyl-naphthalen-2-yloxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

A solution of the material from preparation 1 (120 mg, 0.37 mmol),triphenylphosphine (145 mg, 0.55 mmol), ethyl3-hydroxy-naphthalen-2-carboxylate (111 mg, 0.55 mmol) intetrahydrofuran (1.9 ml), was treated with diethylazodicarboxylate(0.090 mL, 0.55 mmol) at room temperature for 16 h. Flash chromatography(silicagel, 50% diethyl ether/hexane) gave 103 mg of the titleintermediate (55%).

B. Preparation of (3S, 4aR, 6S, 8aR)6-(3-Carboxy-naphthalen-2-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To a solution of the material from step A (103 mg, 0.20 mmol) intetrahydrofuran (0.5 mL) hydrochloric acid (3N, 1 mL) was added. Theresulting mixture was stirred at 80° C. for 10 h and concentrated invacuo to give a solid that was triturated with ethyl acetate, diethylether and cold acetone to afford the desired aminoacid (57 mg, 70%).

Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 370.2

¹H NMR (CD₃OD, 200.13 MHz): 8.35 (s, 1H); 7.83 (t, J=7.9 Hz, 2H); 7.48(m, 3H); 4.63 (m, 1H); 4.10 (m, 1H); 3.40 (m, 1H); 3.15 (m, 1H);2.26-1.55 (m, 10H).

EXAMPLE 2 Preparation of (3S, 4aR, 6S, 8aR)6-(4-carboxy-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 1, step A, a solutionof the material from preparation 1 (2.02 g, 8.3 mmol),triphenylphosphine (3.15 g, 12.0 mmol), ethyl3-hydroxy-biphenyl-4-carboxylate (2.63 g, 8.02 mmol) in tetrahydrofuran(42 mL), was treated with diethylazodicarboxylate (1.89 mL, 12.0 mmol)at room temperature for 20 h. Flash chromatography (silicagel, 30%diethyl ether/hexane) gave 2.76 g of the title intermediate (62%).

Mass Spectrum (Fast Atom Bombardement) M+Na: 574.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-(4-carboxy-biphenyl-3-yloxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

To a solution of the material from step A (400 mg) in absolute ethanol(2 mL) a solution of lithium hydroxide (2.5 N, 2 mL) was added. Theresulting mixture was stirred at room temperature for 72 hours. Theethanol was removed in vacuo and the mixture extracted with ethylacetate (2×). The aqueous phase was made acidic by addition ofhydrochloric acid (10%, pH=3-4) and extracted with ethyl acetate (3×).The resulting organic phases were combined, dried and concentrated invacuo to afford, after flash chromatography (silicagel, 50% ethylacetate/hexane/5% acetic acid), to give the title compound (350 mg, 95%)

Mass Spectrum (Fast Atom Bombardement) M+1: 496.2

C. Preparation of (3S, 4aR, 6S, 8aR)6-(4-carboxy-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

The material from step B (350 mg, 0.71 mmol) was treated with ethylacetate saturated with hydrogen chloride (7 mL) for 4 hours at roomtemperature. The mixture was concentrated in vacuo to afford, aftertrituration with ethyl acetate and diethyl ether, the desired aminoacid(250 mg, 82%).

Ion Electrospray Mass Spectrum M-HCl+1: 396.2

¹H NMR (CD₃OD, 200.13 MHz): 7.90 (d, J=8.1 Hz, 1H); 7.78 (m, 2H);7.53-7.27 (m, 5H); 4.60 (m, 1H); 4.08 (dd, J=12.03.3 Hz, 1H); 3.37 (m,1H); 3.12 (dd, 3=12.7, 4.3Hz, 1H); 2.18-1.59 (m, 10H).

EXAMPLE 3 Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

A. Preparation of ethyl (35, 4aR, 6S, 8aR) 6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

Following the procedures as described in Example 2C, material fromExample 2A (2.25 g, 4.08 mmol) treated with ethyl acetate saturated withhydrogen chloride (50 mL) gave a solid that was washed with hexane toafford the title compound (1.9 g, 95%).

Ion Electrospray Mass Spectrum M-HCl+1: 452.2

Analysis calcd. for: C27H33NO5.1 HCl. 0.8H2O: C 64.55, H, 7.14, N, 2.79;Found: C 64.64, H 7.34, N 3.00.

EXAMPLE 4 Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-5-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 1, step A, a solutionof the material from preparation 1A (120 mg, 0.37 mmol),triphenylphosphine (145 mg, 0.55 mmol), ethyl4-chloro-2-hydroxy-benzoate (80 mg, 0.40 mmol) in tetrahydrofuran (1.9mL), was treated with diethylazodicarboxylate (0.090 mL, 0.55 mmol) at70° C. for 24 h. Flash chromatography (silicagel, 40% diethylether/hexane) gave 132 mg of the title intermediate (71%).

Mass Spectrum (Fast Atom Bombardement) M+1: 510.3

B. Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-5-chloro-2-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 2B, a solution of thematerial from step A (132 mg, 0.26 mmol) in tetrahydrofuran (1.2 mL) andabsolute ethanol (0.5 mL) was treated with a solution of lithiumhydroxide (2.5 N, 1 mL) at room temperature for 24 h to give the titlecompound (118 mg, 100%).

Mass Spectrum (Fast Atom Bombardement) M+Na: 476.2

C. Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-5-chloro-2-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 2C, material from stepB (118 mg, 0.26 mmol) treated with ethyl acetate saturated with hydrogenchloride (1 mL) gave the desired aminoacid (98 mg, 97%).

Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 354.1

Analysis calcd. for: C17H202NO5.1 HCl. 0.5H2O: C, 51.14; H, 5.55; N,3.51; Found: C 51.37, H 5.90, N 3.82.

EXAMPLE 5 Preparation of ethyl (35, 4aR, 6S, 8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

A. Preparation of ethyl (3S, 4aR, 65, 8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

Following the procedures as described in Example 2 step C, material fromExample 4, step A (1.25 g, 2.45 mmol) treated with ethyl acetatesaturated with hydrogen chloride (20 mL) gave the title compound (930mg, 93%).

Ion Electrospray Mass Spectrum M-HCl+1: 410.2

¹H NMR (CDCl₃, 200.13 MHz): 9.85 (br s, 2H); 7.64 (d, J=8.2 Hz, 1H);6.90 (m, 2H); 5.28 (br s, 1H); 4.24 (m, 5H); 3.91 (br s, 1H); 3.42, 3.26(2 br s, 2H); 2.65-1.78 (m, 10H); 1.32-1.18 (m, 6H).

EXAMPLE 6 Preparation of (35, 4aR, 6S, 8aR)6-(2-carboxy-4,5-difluoro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonyl-4,5-difluoro-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 1, step A, a solutionof the material from preparation 1A (100 mg, 0.31 mmol),triphenylphosphine (121 mg, 0.46 mmol), ethyl4,5-difluoro-2-hydroxy-benzoate (78 mg, 0.39 mmol) in tetrahydrofuran(1.6 mL), was treated with diethylazodicarboxylate (0.072 mL, 0.46 mmol)at room temperature for 36 h. Flash chromatography (silicagel, 40%diethyl ether/hexane) gave 115 mg of the title intermediate (73%).

Ion Electrospray Mass Spectrum M+Na: 534.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-4,5-difluoro-2-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 2B, a solution of thematerial from step A (99 mg, 0.21 mmol) in absolute ethanol (1 mL) wastreated with a solution of lithium hydroxide (2.5 N, 1 mL) at roomtemperature for 48 h to give the title compound (87 mg, 100%).

Mass Spectrum (Fast Atom Bombardement) M+Na: 478.2

C. Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-4,5-difluoro-2-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 2 step C, material fromstep B (77 mg, 0.17 mmol) treated with ethyl acetate saturated withhydrogen chloride (2 mL) gave, after washing the solid with diethylether and acetone, the desired aminoacid (98 mg, 97%).

Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 356.1

¹H N (CD₃OD, 200.13 MHz): 7.70 (t, J=9.9 Hz, 1H); 7.21 (dd, J=6.6, 5.8Hz, 1H); 4.44 (m, 1H); 4.07 (br d, J=14.4 Hz, 1H); 3.35 (m, 1H); 3.16(dd, J=12.5, 3.7 Hz, 1H); 2.23-1.49 (m, 10H).

EXAMPLE 7 Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonyl-4-chloro-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 1, step A, a solutionof the material from preparation 1 (120 mg, 0.37 mmol),triphenylphosphine (145 mg, 0.55 mmol), ethyl2-hydroxy-5-chloro-benzoate (73 mg, 0.366 mmol) in tetrahydrofuran (2mL), was treated with diethylazodicarboxylate (0.090 mL, 0.55 mmol) atroom temperature for 16 h. Flash chromatography (silica gel, diethylether-hexane 1:2) gave 106 mg (57% yield) of the title compound.

Mass Spectrum (Fast Atom Bombardement) M+1:511.1

B. Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-4-chloro-phenoxy)-1,2,3,4,a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A solution of the material from step A (106 mg, 0.20 mmol) intetrahydrofuran (1 mL) was treated with 3N HCl (3 mL) and heated at 80°C. overnight. The crude was concentrate in vacuo and washed with ethylacetate gel, to afford 25 mg (31% yield) of the title compound.

Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 354.1

Analysis calculated for C17H21Cl2NO5: % C, 52.32; % H, 5.42; % N, 3.59.Found: % C, 52.39; % H, 5.61; % N, 3.60.

EXAMPLE 8 Preparation of (3S, 4aR, 6S, 8aR)6-(2-carboxy-4-nitro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(2-ethoxycarbonyl-4-nitro-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinohne-3-carboxylate

Following the procedures as described in Example 1A, a solution of thematerial from preparation 1A (120 mg, 0.37 mmol), triphenylphosphine(145 mg, 0.55 mmol), ethyl 2-hydroxy-5-nitro-benzoate (77 mg, 0.366mmol) in tetrahydrofuran (2 mL), was treated withdiethylazodicarboxylate (0.090 mL, 0.55 mmol) at room temperature for 16h. Flash chromatography (silica gel, diethyl ether-hexane 1:2) gave 120mg (63% yield) of the title compound.

Mass Spectrum (Fast Atom Bombardement) M+1:521.3

B. Preparation of (3S, 4aR, 65, 8aR)6-(2-carboxy-4-nitro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 7, step B, compoundfrom step A (106 mg, 0.23 mmol) afforded 50 mg (54% yield) of the titlecompound.

Mass Spectrum (Fast Atom Bombardement) M-HCl+1: 365.1

Analysis calculated for C17H21ClN2O7: % C, 50.94; % H, 5.28; % N, 6.99.Found: % C, 50.88; % H, 5.35; % N, 6.80.

Preparation 2 (3S, 4aR, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A. Ethyl (3S, 4aR, 8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of ethyl (3S, 4aR, 6R, 8aR)6-oxo-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate(3.54 g, 12.5 mmol) in methylene chloride (100 mL) under nitrogen,iodotrimethylsilane (10.0 g, 50 mmol) was added in one portion at roomtemperature. The reaction mixture was stirred overnight and quenchedwith ethanol (20-30 mL). The solution was concentrated in vacuo anddried for 3 hours under reduced pressure. The resulting solid wasdissolved in methylene chloride (100 mL) and triethylamine (7 mL, 50mmol) was added. After stirring for 15 minutes a solution ofdi-tert-butyl-dicarbonate (2.73 g, 12.5 mmol) in methylene chloride(10mL) was added. The resulting mixture was stirred overnight at roomtemperature and concentrated in vacuo. The resulting solid was suspendedin ethyl acetate and filtered. The filtrate was washed with 1Nhydrochloric acid and brine. The organic phase was dried, filtered andconcentrated in vacuo. Flash chromatography (silicagel, 25% ethylacetate/hexane) gave pure product as an colorless oil (3.69 g, 92%).

B. (3S, 4aR, 8aR)6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

To a solution of ester from preparation 2A (9.7 g, 29.81 mmol) inabsolute ethanol (130 mL) a solution of lithium hydroxide (2.5 N, 132mL) was added. The resulting mixture was stirred at room temperature for22 h. The ethanol was removed in vacuo and the resulting mixture waswashed with ethyl acetate (x2). The aqueous phase was made acidic byaddition of 10% hydrochloric acid (pH=3-4) and extracted with ethylacetate (x3). The resulting organic phases were combined, dried andconcentrated in vacuo to afford the title compound (8.85 g, 100%)

C. (3S, 4aR, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

To an ice-cooled solution of ketone from preparation 2B (11.34 g, 38.14mmol) in dry tetrahydrofuran (50 mL) under nitrogen a solution ofL-Selectride (1 M in tetrahydrofuran, 76 mL) was added dropwise. Theresulting mixture was allowed to reach room temperature for 2 h andquenched with 1N hydrochloric acid (78 mL). To the resulting mixturesodium chloride was added to saturate the aqueous phase. Afterfiltration the aqueous phase was extracted with ethyl acetate. Thecombined organic phases were dried and concentrated in vacuo. Hashchromatography (silicagel, ethyl acetate-hexane 4:3) afforded thedesired alcohol (8.5 g, 74%)

EXAMPLE 9 Preparation of (3S, 4aR, 6S, 8aR)6-[3-Chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)&(3-chloro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

To an ice-cooled solution of the material from preparation 2 (400 mg,1.34 mmol) in dry tetrahydrofuran (5.6 mL) under nitrogen a solution ofpotassium tert-butoxide (1M in tetrahydrofuran, 3.0 mL) was slowlyadded. The resulting suspension was stirred at room temperature for 25min and again cooled to 0-5° C. before the addition of2-chloro-6-fluorobenzonitrile (249 mg, 1.60 mmol). The reaction mixturewas stirred a room temperature overnight, diluted with water and washedwith ethyl acetate (x2). The aqueous phase was made acidic (pH=3-4) with10% hydrochloric acid and extracted with ethyl acetate (x2). Theresulting organic phases were combined, dried and concentrated in vacuo.Flash chromatography (silicagel, 75% ethyl acetate/hexane/2.5% aceticacid) gave the desired compound as a white solid (460 mg, 79%).

Ion Electrospray Mass Spectrum M+1-t-butylOCO: 335.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A mixture of the nitrile from Example 9, step A (3.03 g, 6.9 mmol) andazidotri-n-butylstannane (7.6 mL, 28 mmol) was stirred under nitrogen at85° C. for 60 h. The mixture was diluted with ethyl acetate (20 mL) andsodium hydroxide (2.5N, 25 mL) was added. The resulting mixture wasstirred for 1 h. The aqueous layer was washed with ethyl acetate (2×)and concentrated in vacuo. Flash chromatography (silicagel, 55% ethylacetate/hexane/1% acetic acid) gave the desired tetrazol as an oil (1.18g, 35%).

Ion Electrospray Mass Spectrum M+1: 478.1

C. Preparation of (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A suspension of the protected decahydroisoquinoline from step B (400 mg,0.84 mmol) in ethyl acetate saturated with hydrogen chloride (5 mL) wasstirred for 4 h at room temperature. The mixture was extracted withwater (1×). The aqueous layer was washed with ethyl acetate (2×) andconcentrated in vacuo to afford a white solid (320 mg, 92%).

Ion Electrospray Mass Spectrum M-HCl+1: 378.11

¹H NMR (CD₃OD, 200.13 MHz): 7.54 (t, J=8.3 Hz, 1H); 7.22 (t, J=8.1 Hz,2H); 4.47 (m, 1H); 4.00 (dd, J=12.6, 3.5 Hz, 1H); 3.21 (t, J=12.6 Hz,1H); 3.06 (dd, J=12.7, 4.7 Hz, 1H); 2.21-1.59 (m, 10H).

EXAMPLE 10 Preparation of 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

To a suspension of the compound from Example 9, step C (900 mg, 2.18mmol) in 2-ethylbutanol (50 mL), thionyl chloride (1.75 mil, 24 mmol)was added dropwise. The resulting solution was stirred at 120° C. for 2h. The solvent was removed in vacuo and diethyl ether was added. Theresulting solid was filtered and washed with (#ethyl ether) to give thedesired material (711 mg, 70%).

Ion Electrospray Mass Spectrum M-HCl+1: 462.3

¹H NMR (CD₃OD, 200.13 MHz): 7.53 (t, J=8.0 Hz, 1H); 7.24 (d, J=8.2 Hz, 1H); 7.19 (d, J=8.0 Hz, 1H); 4.45 (br s, 1H); 4.22 (dd, J=10.8, 5.7 Hz,1H); 4.14 (m, 2H); 3.23 (t, J=12.6 Hz, 1H); 3.11 (d, J=9.6 Hz, 1H);2.19-1.36 (m, 15H); 0.91 (t, J=7.5 Hz, 6H).

EXAMPLE 11 Preparation of (3S, 4aR, 6S, 8aR)6-[3-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(3-methoxy-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (400 mg, 1.34 mmol) in tetrahydrofuran (5.6 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 3.0 mL) and 6-methoxy-2-fluorobenzonitrile (242 mg,1.60 mmol) to give, after flash chromatography (silicagel, 75% ethylacetate/hexane/2.5% acetic acid), 429 mg of the title compound (74%).

Ion Electrospray Mass Spectrum M+1-t-butylOCO: 331.3

B. Preparation of (3S, 4aR, 6S, 8aR)6-[3-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9, step B, compoundfrom step A (429 mg, 0.92 mmol) was treated withazidotri-n-butylstannane (0.8 mL, 3.6 mmol) at 85° C. for 62 h to give50 mg of an oil that was directly submitted to the next reaction. As forExample 2, step C, the above material was treated with ethyl acetatesaturated with hydrogen chloride (2.5 mL) to give the desired aminoacid(17 mg, 5%, two steps).

Ion Electrospray Mass Spectrum M-HCl+1: 374.2

¹H NMR (CD₃OD, 200.13 MHz): 7.50 (t, J=8.5 Hz, 1H); 6.82 (dd, J=12.0,8.5 Hz, 2H); 4.43 (m, 1H); 4.02 (dd, J=12.3, 3.6 Hz, 1H); 3.81 (s, 3H);3.22 (d, J=12.8 Hz, 1H); 3.07 (dd, J=12.8, 4.3 Hz, 1H); 2.14-1.29 (m,10H).

EXAMPLE 12 Preparation of (3S, 4aR, 6S, 8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(3-fluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (300 mg, 1 mmol) in tetrahydrofuran (4.2 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 2.2 mL) and 2,6 difluorobenzonitrile (209 mg, 1.5 mmol)to give 377 mg of the title compound (90%).

Ion Electrospray Mass Spectrum M+Na: 441.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)phenoxy]-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step B, compoundfrom step A (370 mg, 0.88 mmol) was treated withazidotri-n-butylstannane (1.0 mL, 3.6 mmol) at 90° C. for 31 h to givethe desired compound (120 mg, 29%).

Ion Electrospray Mass Spectrum M+1: 462.3

C. Preparation of (3S, 4aR, 6S, 8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9, step C, materialfrom step B (120 mg, 0.26 mmol) treated with ethyl acetate saturatedwith hydrogen chloride (3 mL) gave the desired aminoacid (60 mg, 64%).

Ion Electrospray Mass Spectrum M-HCl+1: 362.2

¹H NMR (CD₃OD, 200.13 MHz): 7.57 (dt, J=8.3, 6.7 Hz, 1H); 7.13 (d, J=8.9Hz, 1H); 6.97-6.88 (m, 1H); 4.59-4.49 (m, 1H); 4.05 (dd, J=12.1, 4.3-Hz,1H); 3.38-3.25 (m, 1H); 3.11 (dd, J=12.9, 4.6 Hz, 1H); 2.27-1.39 (m,10H).

EXAMPLE 13 Preparation of (3S, 4aR, 6S, 8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinohne-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(4-fluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (300 mg, 1 mmol) in tetrahydrofuran (4.2 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 2.2 mL) and 2,5-difluorobenzonitrile (209 mg, 1.5 mmol)to give 344 mg of the title compound (82%).

Ion Electrospray Mass Spectrum M+Na: 441.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step B, compoundfrom step A (344 mg, 0.82 mmol) was treated withazidotri-n-butylstannane (0.9 mL, 3.3 mmol) at 90° C. for 24 h to givethe desired compound (249 mg, 66%).

Ion Electrospray Mass Spectrum M+1: 462.3

C. Preparation of (3S, 4aR, 6S, 8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9, step C, materialfrom step B (249 mg, 0.54 mmol) treated with ethyl acetate saturatedwith hydrogen chloride (2.5 mL) gave the desired compound (70 mg, 36%)

Ion Electrospray Mass Spectrum M-HCl+1: 362.2

¹H NMR (CD₃OD, 200.13 MHz): 7.70 (dt, J=8.4, 1.9H, 1 H); 7.33 (dd,J=5.9, 1.5 Hz, 2H); 4.54 (m, 1H); 4.02 (dd, J=12.2, 4.2 Hz, 1H);3.42-3.30 (m, 1H); 3.14 (dd, J=12.8, 4.4 Hz, 1H); 2.17-1.52 (m, 10H).

EXAMPLE 14 Preparation of (3S, 4aR, 6S, 8aR)6-[4-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(4-methyl-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (170 mg, 0.57 mmol) in tetrahydrofuran (2.4 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 1.2 mL) and 5-methyl-2-fluorobenzonitrile (85 mg, 0.62mmol) to give, after flash chromatography (silicagel, 60% ethylacetate/hexane/2.5% acetic acid), 187 mg of the title compound (79%).

Ion Electrospray Mass Spectrum M+1: 415.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-[4-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9, step B, compoundfrom step A (147 mg, 0.36 mmol) was treated withazidotri-n-butylstannane (0.44 mL, 1.5 mmol) at 90° C. for 64 h to givea solid (80 mg, 49%) that was directly submitted to the next reaction.The solid was treated with ethyl acetate saturated with hydrogenchloride (1 mL) and hydrochloric acid (1 mL) to give the desiredaminoacid (37 mg, 29%, two steps)

Ion Electrospray Mass Spectrum M-HCl+1: 358.3

¹H NMR (CD₃OD, 500 MHz): 7.79 (s, 1H); 7.35 (d, J=7.1 Hz, 1H); 7.18 (d,J=8.6 Hz, 1H); 4.54 (m, 1H); 4.07 (d, J=11.1 Hz, 1H); 3.40 (t, J=12.9Hz, 1H); 3.14 (d, J=9.5 Hz, 1H); 2.34 (s, 3H); 2.32-1.57 (m, 10H).

EXAMPLE 15 Preparation of (3S, 4aR, 6S, 8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(5-bromo-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (350 mg, 1.17 mmol) in tetrahydrofuran (4.9 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 2.6 mL) and 5-methyl-2-fluorobenzonitrile (281 mg, 2.34mmol) to give, after flash chromatography (silicagel, 70% ethylacetate/hexane/2.5% acetic acid), 470 mg of the title compound (72%).

Ion Electrospray Mass Spectrum M+Na: 501.0

B. Preparation of (3S, 4aR, 6S, 8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Following the procedures as described in Example 9, step B, compoundfrom step A (468 mg, 0.98 mmol) was treated withazidotri-n-butylstannane (1.1 mL, 3.92 mmol) at 85° C. for 30 h to givethe desired compound (380 mg, 74. %).

Ion Electrospray Mass Spectrum M+1: 522.1

C. Preparation of (3S, 4aR, 6S, 8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9, step C, materialfrom step B (378 mg, 0.72 mmol) treated with ethyl acetate saturatedwith hydrogen chloride (6 mL) gave the desired aminoacid (290 mg, 95%)

Ion Electrospray Mass Spectrum M-HCl+1: 422.0

Analysis calcd. for: C17H20BrN5O3.1 HCl. 1.5H2O: C, 42.03; H, 4.98; N,14.42; Found: C, 41.75; H, 4.59; N, 14.02.

EXAMPLE 16 Preparation of (3S, 4aR, 6S, 8aR)6-[3,5-difluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4aR, 6S, 8aR)6-(3,5-difluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinohne-3-carboxylicacid

Following the procedures as described in Example 9, step A, materialfrom preparation 2 (150 mg, 0.50 mmol) in tetrahydrofuran (2.0 mL) wastreated with a solution of potassium tert-butoxide (1 M intetrahydrofuran, 1.1 mL) and 2,4,6-trifluorobenzonitrile (102 mg, 0.65mmol) to give, after flash chromatography (silicagel, 50% ethylacetate/hexane/0.5% acetic acid), 75 mg of the title compound (35%).

Ion Electrospray Mass Spectrum M+Na: 459.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-[3,5-difluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To the compound from step A (75 mg, 0.17 mmol), toluene (0.2 mL) andazidotri-n-butylstannane (140 □L, 0.51 mmol) were added at roomtemperature. The reaction mixture was allowed to stir at 100° C. forfour days. Then, it was cooled at room temperature and treated with a 1Nsolution of hydrogen chloride in ethyl acetate(5 mL). The reactionmixture was allowed to stir at room temperature for 2 hours. Theresulting white solid was washed with ethyl acetate and ethyl ether togive, after purification by HPLC [YMC C18, 2×5 cm, (A) water/0.05%trifluoroacetic acid, (B) acetonitrile/0.05% trifluoroacetic acid; 10mL/min, 5-40% B in 15 min] the desired aminoacid (6 mg, 9%, two steps).

Ion Electrospray Mass Spectrum M-HCl+1: 380.2

¹H-NMR (MeOH-d4, 200.15 MHz): 7.02 (dd, J=11.0, 1.6 Hz, 1H); 6.87-6.76(m, 1H); 4.59-4.39 (m, 1H); 4.02 (dd, J=12.6, 3.8 Hz, 1H); 3.21-3.05 (m,2H); 2.20-1.78 (m, 8H); 1.49-1.29 (m, 2H).

EXAMPLE 17 Preparation of (3S, 4aR, 6S, 8aR) 6-[4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-caboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(4-chloro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of the material from preparation 1 (120 mg, 0.37 mmol),triphenylphosphine (145 mg, 0.55 mmol) and5-chloro-2-hydroxy-benzonitrile (136 mg, 0.89 mmol) in drytetrahydrofuran (1.9 mL) under nitrogen, neat diethylazodicarboxylate(0.090 mL, 0.55 mmol) was added dropwise at room temperature. Thereaction mixture was stirred overnight at room temperature andconcentrated in vacuo. Flash chromatography (silicagel, 25% ethylacetate/hexane) gave 61 mg of the desired compound(36%).

Ion Electrospray Mass Spectrum M+1: 463.2

B. Preparation of (3S, 4aR, 6S, 8aR)6-(4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A mixture of the material from step A (120 mg, 0.26 mmol) andazidotri-n-butylstannane (0.21 mL, 0.78 mmol) was stirred under nitrogenat 50° C. for 76 h and at 70° C. overnight. The reaction mixture wasdirectly treated with ethanol (2 mL) and lithium hydroxide aqueoussolution (40%, 2.5 mL) and stirred at room temperature for 24 h. Thereaction mixture was diluted with water and washed with ethyl acetate(2×). The aqueous layer was made acidic by addition of hydrochloric acid(10%, till pH=5-6) and extracted with ethyl acetate (3×). The combinedorganic phases were dried and concentrated in vacuo to afford the titlecompound as a foam (98 mg, 79%, two steps).

Ion Electrospray Mass Spectrum M+1: 478.2

C. Preparation of (3S, 4aR, 6S, 8aR)6-[4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

The material from step B (95 mg, 0.2 mmol) was treated with hydrochloricacid (5N, 1.5 mL) at room temperature for 5 h to give, after triturationwith ethyl acetate and diethyl ether, the desired aminoacid (37 mg, 49%)

Ion Electrospray Mass Spectrum M-HCl+1: 378.1

¹H NMR (CD₃OD, 200.13 MHz): 7.95 (d, J=2.6 Hz, 1H); 7.54 (dd, J=9.0, 2.6Hz, 1H); 7.32 (d, J=9.0 Hz, 1H); 4.59 (m, 1H); 4.14 (dd, J=13.4, 2.7 Hz,1H); 3.22 (dd, J=13.0, 4.4 Hz, 1H); 2.21-1.65 (m, 10H).

EXAMPLE 18 Preparation of (35, 4aR, 6S, 8aR)6-[5-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(5-methyl-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of the material from preparation 1 (200 mg, 0.61 mmol),triphenylphosphine (192 mg, 0.73 mmol), 4-methyl-2-hydroxy-benzonitrile(89 mg, 0.67 mmol) and dry pyridine (0.055 mL, 0.67 mmol) in drytetrahydrofuran (3.1 mL) under nitrogen, neat diethylazodicarboxylate(0.115 mL, 0.73 mmol) was added dropwise at 0° C. The reaction mixturewas stirred for 48 h at room temperature and concentrated in vacuo. Asolution of the material in methylene chloride was washed with sodiumhydroxide aqueous solution (0.5 M, x2), dried and evaporated in vacuo.Flash chromatography (silicagel, 25% ethyl acetate/hexane) gave 86 mg ofthe desired compound (32%).

Ion Electrospray Mass Spectrum M+1-t-butylOCO: 343.3

B. Preparation of (3S, 4aR, 6S, 8aR)6-[5-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 17, step B the materialfrom step A (70 mg, 0.15 mmol) was treated with azidotri-n-butylstannane(0.125 mL, 0.45 mmol) at 85° C. for 76 h and then treated with ethanol(1.5 mL) and lithium hydroxide aqueous solution (40%, 2 mL) for 48 h toafford a material (33 mg) that was directly submitted to the nextreaction. The above material was treated with ethyl acetate saturatedwith hydrogen chloride (2 mL) at room temperature for 4 h to give, aftertrituration with ethyl acetate and diethyl ether, the title compound (17mg, 65%, three steps)

Ion Electrospray Mass Spectrum M+1: 358.3

¹H NMR (CD₃OD, 200.13 MHz): 7.86 (d, I=7.9H-z, 1H); 7.14 (s, 1H);6.96(d, J=7.9 Hz, 1H); 4.89 (m, 1H); 4.09 (dd, J=12.3, 3.7 Hz, 1H); 3.42(t, J=13.0 Hz, 1H); 3.15 (dd, J=12.9, 4.1 Hz, 1H); 2.43 (s, 3H);2.21-1.51 (m, 10H).

EXAMPLE 19 Preparation of (3S, 4aR, 6S, 8aR) 6-[5-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(5-methoxy-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 18, step A, a solutionof the material from preparation 1, triphenylphosphine,4-methoxy-2-hydroxy-benzonitrile (100 mg, 0.67 mmol) and pyridine intetrahydrofuran, was treated with diethylazodicarboxylate at roomtemperature for 24 h. Flash chromatography (silicagel, 35% ethylacetate/hexane) gave 150 mg of the desired compound (54%).

Ion Electrospray Mass Spectrum M+Na: 481.1

B. Preparation of (3S, 4aR, 68, 8aR)6-[5-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 17, step B the materialfrom step A (125 mg, 0.27 mmol) was treated withazidotri-n-butylstannane (0.225 mL, 0.82 mmol) at 85° C. for 45 h andthen treated with ethanol (2 mL) and lithium hydroxide aqueous solution(40%, 2.5 mL) for 48 h to afford an oil (79 mg) that was directlytreated with ethyl acetate saturated with hydrogen chloride (2 mL) togive the title compound (45 mg, 41%, three steps)

Ion Electrospray Mass Spectrum M+1: 374.2

Analysis calcd. for: C18H23N5O4.1.7 HCl.0.2 CH3CH2OH: C, 49.71; H, 5.87;N, 15.75;

Found: C, 50.05; H, 5.52; N, 15.51.

EXAMPLE 20 Preparation of (3S, 4aR, 6S, 8aR)6-[2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A. Preparation of ethyl (38, 4aR, 6S, 8aR)6-(2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described in Example 18, step A, a solutionof the material from preparation 1 (400 mg, 1.22 mmol),triphenylphosphine (384 mg, 1.46 mmol), 2-hydroxy-benzonitrile (160 mg,1.34 mmol) and pyridine (0.11 mL, 1.34 mmol) in tetrahydrofuran (6.1mL), was treated with diethylazodicarboxylate (0.23 mL, 1.46 mmol) atroom temperature for 43 h. Flash chromatography (silicagel, 35% ethylacetate/hexane) gave 264 mg of the desired intermediate (51%).

Mass Spectrum (Fast Atom Bombardement) M+1: 429.3

B. (3S, 4aR, 6S, 8aR)6-[2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

The intermediate from step A (45 mg, 0.105 mmol), was treated withazidotributyltin (0.17 mL, 0.626 mmol) and heated at 80° C. for threedays. The mixture was concentrated in vacuo and treated with 2.5 Mlithium hydroxide solution (3 mL) and heated at 50° C. overnight. Thenthe mixture was extracted with ethyl acetate and the aqueous phase wasseparated and treated with ethyl acetate saturated with hydrogenchloride and extracted. The aqueous phase was concentrated in vacuo, theproduct was dissolved in water and then Dowex resin (2.0 g) was addedand stirred for 1 h. The resin was washed with water and 50 mL 1:1tetrahydrofuran/water. The resin was collected, a 10% solutionpyridine-water was added and the mixture was stirred for 2 hours,filtered and the filtrate was collected. The resin was washed with water(10 mL) and the combined pyridine-water filtrate was concentrated invacuo to give 18 mg (50% yield) of the title compound.

Mass Spectrum (East Atom Bombardement) M+1: 344.2

¹H NMR (CD₃OD, 200.13 MHz): 7.54 (m, 1H); 7.33 (m, 1H); 7.13 (m, 2H);4.12 (m, 1H); 3.22 (m, 1H); 2.95 (m, 1H); 2.59 (m, 1H); 2.10-1.39 (m,10H).

EXAMPLE 21 Preparation of (3S, 4aR, 6S, 8aR)6-[5-Benzyloxy-3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. 4-Benzyloxy-2,6-difluorobenzonitrile

To a suspension of 2,4,6-trifluorobenzonitrile (314 mg, 2.00 mmol) andpotassium carbonate (828 mg, 6.00 mmol) in dry N,N-dimethylformamide (3mL) at 100° C. was added a solution of benzyl alcohol (216 mg, 2.00 mL)in dry N,N-dimethylformamide (1 mL) using a syringe pump over 4 h andthe resulting mixture was stirred at 100° C. for 1 h. The reactionmixture was stirred at room temperature overnight and water and ethylacetate were added and the phases separated. The organic phase waswashed with 1.2 M hydrochloric acid (3×) and the combined organic phaseswere back-extractted with ethyl acetate (3×). The organic phases weredried (sodium sulfate), filtered, concentrated in vacuo and the residuewas purified by flash chromatography (silica gel, hexanes-ethyl acetate15:1) to give a white solid, mixture of regioisomers. The title productwas obtained as a white solid (51 mg, 10%) by HPLC purification(reversed phase).

Ion Electrospray Mass Spectrum M+18: 263.

B. Preparation of ethyl (3S, 4aR, 6S, 8aR)6-(5-benzyloxy-3-fluoro-2-cyano-phenoxy)-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures as described for Example 9, step A, reaction ofmaterial from step A (51 mg, 0.21 mmol) with Preparation 1 (52 mg, 0.18mmol) and potassium tert-butoxide (0.40 mL, 0.40 mmol) intetrahydrofuran (2 mL) gave, after flash chromatography (silica gel,hexanes-ethyl acetate-acetic acid: 1:1:0.01) the desired product as awhite solid (58 mg) in 61% yield.

Ion Electrospray Mass Spectrum M+Na: 547

C. Preparation of (3S, 4aR, 6S, 8aR)6-[5-Benzyloxy-3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

As for Example 9, step B, the reaction between material from step B (58mg, 0.11 mmol) and azido tributyltin (8 equiv, 292 mg, 0.88 mmol) at 90°C. for 5 d gave the desired tetrazol. The crude product was disolved in1 M hydrogen chloride/ethyl acetate solution (5 mL) and the mixture wasstirred at room temperature 2 h and filtered. The solid was washed withethyl, dried and purified by solid-phase extraction to give pureaminoacid as a pale yellow solid (25 mg, 45%) and small amount (7 mg,13%) slightly impure.

Ion Electrospray Mass Spectrum M+1: 568.

Preparation 3

Preparation of ethyl (3S, 4aR, 6R, 8aR)6-methanesulfonyloxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To an ice-cooled solution of ethyl (3S, 4aR, 6R, 8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate(760 mg, 2.66 mmol) in dry dichloromethane (10 mL) under nitrogen,triethylamine (0.60 mL, 4.3 mmol) and methanesulfonyl chloride (0.33 mL,4.3 mmol) were added. The resulting mixture was stirred overnight atroom temperature and a saturated solution of ammonium chloride was added(10 mL). The layers were separated and the aqueous layer extracted withdichloromethane (10 mL×2). The combined organic phases were washed with1 N hydrochloric acid (10 mL), dried over sodium sulfate andconcentrated in vacuo to give the title compound as an oil (0.965 g,100%).

Ion Electrospray Mass Spectrum M+1: 364

EXAMPLE 22 Preparation of (3S, 4aR, 6S, 8aR)6-((3-carboxy-2-naphthalenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Methyl-3-(((trifluoromethane)sulfonyl)oxy)-2-naphthoate.

To a solution of methyl 3-hydroxy-2-naphtoate (500 mg, 2.47 mmol) and4-(N,N-dimethylamino)pyridine (603 mg, 4.94 mmol) in dichloromethane (25mL) at 0° C. under nitrogen, trifluoromethanesulfonic anhydride (677 mg,0.404 mL, 2.97 mmol) was added dropwise and the reaction mixture wasstirred for 10 min at 0° C. and then at room temperature until nostarting material is left according to TLC (hexane-ethyl acetate 9:1) (asecond addition of 0.1-0.2 equiv of trifluoromethanesulfonic anhydridemight be required). The reaction mixture was treated with saturatedaqueous solution of ammonium chloride and the phases separated. Theorganic phase was washed twice with saturated aqueous solution ofammonium chloride and the aqueous were phases back-extracted withdichloromethane. The combined organic phases were washed with brine,treated with a spoon of silica gel to remove trazes ofN,N-dimethylaminopyridine, dried with anhydrous sodium sulfate, filteredand concentrated in vacuo, to afford the desired triflate inquantitative yield (845 mg) as a white solid. The product was usedwithout further purification.

Electronic Impact Mass Spectrum M+: 334.

Analysis Calculated for C₁₃H₉F₃O₅S: C, 46.71; H, 2.71

Found: C, 46.54; H, 2.66

B. Methyl 3-mercapto-2-naphthoate

To a carefully deoxygenated solution of the compound from step A (200mg, 0.60 mmol) in dry benzene (2 mL) under nitrogen at room temperature,a solution of tetrakistriphenylphosphine palladium (0) (0.05 equiv, 34mg, 0.03 mmol) and sodium triisopropilsilanethiolate in drytetrahydrofuran [1.3 equiv, prepared from triisopropilsilanethiol (148mg, 0.78 mmol) and sodium hydride (95%, 20 mg, 0.78 mmol) intetrahydrofuran (2 mL) at 0° C. 5-10 min, then 5-10 min at roomtemperature) was added and the reaction mixture was warmed to reflux(bath temp-90° C.) for 1.5 h. The reaction mixture was cooled down andconcentrated in vacuo. The crude residue was dissolved intetrahydrofuran (5 mL) and treated with tetrabutylammonium fluoride (1 Msolution in tetrahydrofuran, 1 equiv, 0.6 mL, 0.6 mmol) at 0° C. andstirred for 45 min. Glacial acetic acid (0.5 mL) was added and thereaction mixture stirred at 0° C. for 15 min. Diethyl ether and waterwere added and the phases separated. The aqueous phase was extractedtwice with diethyl ether and the organic phases dried (sodiumsulfate-magnesium sulfate) filtered and concentrated in vacuo. Flashchromatography (silica gel, hexane-ethyl acetate 25:1) gave the desiredthiol as a white solid (91 mg, 69%).

Electronic Impact Mass Spectrum M+: 218.

C. Ethyl (3S, 4aR, 6S, 8aR)6-((3-methoxycarbonyl-2-naphthalenyl)thio)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of decahydroisoquinoline mesylate from preparation 3 (76mg, 0.21 mmol) in acetone (0.5 mL), potassium carbonate solid (29 mg,0.21 mmol) was added under nitrogen, followed by addition of a solutionof thiol from step B (45 mg, 0.21 mmol) in acetone (0.5 mL) undernitrogen, and the resulting yellow suspension stirred under reflux for 7h. More potassium carbonate solid (29 mg, 0.21 mmol) and more thiol fromstep B (45 mg, 0.21 mmol) in acetone (0.5 mL) were added and the mixturestirred under reflux overnight. The reaction mixture was cooled down andconcentrated in vacuo. Flash chromatography (silica gel, hexane-ethylacetate 2.5:1) gave the desired product (36.5 mg, 36% yield).

¹H NMR (CDCl₃, 200.15 MHz): 8.39 (s, 1H); 7.83 d, J=7.8 Hz, 1H) 7.74 (d,overlapping, 1H); 7.72 (s, 1H); 7.58-7.41 (m, 2H); 4.74 (dd, J=5.8, 3.4Hz, 1H); 4.16 (q, 7.2Hz, 2H); 3.96 (s, 3H); 3.70 (s, 3H); 3.68 (m, 2H);3.30 (br d, J=11Hz, 1H); 2.45 (m, 1H); 2.2-1.7 (m, 8H); 1.45 (m, 1H);1.24 (t, J=7.1 Hz, 3H).

D. (3S, 4aR, 6S, 8aR)6-((3-Carboxy-2-naphthalenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

The alkylated decahydroisoquinoline derivative from step C (36 mg, 0.075mmol) was treated with 6M hydrochloric acid under reflux for 35 h. Thesolution was concentrated in vacuo and water added and concentrated invacuo (3×), followed by addition of acetone and concentration in vacuo(3×), to give an off-white solid (30 mg, 96% yield).

M.p.>183° C. with dec.

Fast Atom Bombardment Mass Spectrum M-Cl+1: 386.

Analysis Calculated for C₂₁H₂₄NO₄S.2H₂O: C, 55.08; H, 6.16; N, 3.06Found: C, 55.08; H, 6.34; N, 3.19

EXAMPLE 23 Preparation of (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazolylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Ethyl (3S, 4aR, 6S, 8aR)6-((2-cyanophenyl)thio)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures for Example 22, Step C, decahydroisoquinolinemesylate from preparation 3 (102 mg, 0.28 mmol) in acetone (0.5 mL),potassium carbonate solid (38 mg, 0.28 mmol, twice) and2-mercaptobenzonitrile (38 mg, 0.286 mmol, twice) gave, after flashchromatography (hexanes-ethyl acetate 2:1), the desired product as anoil (64 mg) in 57% yield.

Electronic Impact Mass Spectrum M+: 402.

B. (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-Tetrazolylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

The alkylated decahydroisoquinoline from step A (122 mg, 0.30 mmol) andazidotributyltin (199 mg, 0.60 mmol) were stirred at 80° C. for 2 days.More azidotributyltin (242 mg, 0.73 mmol) was added and the reactionstirred at 80° C. 3 more days. Diethyl ether and hexane were added andthe oil was washed twice and dried in vacuo. The residue was treatedwith 6M HCl under reflux for 1.5 days. The reaction mixture waselaborated as in example 22, Step D to give the title compound in 98%yield as a pale beige solid.

Fast Atom Bombardment Mass Spectrum M+1: 360

Analysis Calculated for C₁₇H₂₂ClN₅O₂S.3H₂O: C, 45.38; H, 6.27; N, 15.56

Found: C, 45.18; H. 5.82; N, 15.35

EXAMPLE 24 Preparation of (3S, 4aR, 6S, 8aR)6-((2-carboxy-5-methylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Ethyl 4-methyl-2-((trifluoromethyl)sulfonyl)oxy)benzoate

Following the procedures for Example 22, Step A, ethyl4-methylsalicylate (500 mg, 2.77 mmol), 4-(N,N-dimethylamino)pyridine(676 mg, 5.54 mmol) and trifluoromethanesulfonic anhydride (938 mg,0.447 mL, 3.32 mmol) gave the desired triflate as a pale orange oil (760mg, 88% yield). The product was used without further purification.

Electronic Impact Mass Spectrum M+: 312.

Analysis Calculated for C₁₁H₁₁F₃O₅S: C, 42.31; H, 3.55 Found: C, 42.89;H. 3.84

B. Ethyl 2-mercapto-4-methylbenzoate

To a solution of the triflate from step A (500 mg, 1.60 mmol) andtetrakistriphenylphosphine palladium(0) (0.05 equiv, 92 mg, 0.08 mmol)in dry benzene (2 mL) under nitrogen at room temperature, a solution ofsodium triisopropilsilanethiolate in dry tetrahydrofuran [1.3 equiv,prepared from triisopropilsilanethiol (396 mg, 2.08 mmol) and sodiumhydride (95%, 52 mg, 2.08 mmol) in tetrahydrofuran (2 mL) as in Example22, Step B] was added and the reaction mixture was warmed to reflux(bath temp 90° C.) for 3.5 h. The reaction mixture was cooled down to 0°C. and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 1.5equiv, 3.1 mL, 3.1 mmol) and glacial acetic acid (3.5 equiv, 437 mg,0.405 nL, 7.28 mmol) were added and the reaction mixture stirred at 0°C. for 20 min. Work-up as in Example 22, Step B gave, after flashchromatography (silica gel, hexane-ethyl acetate 25:1), the desiredthiol as an oil (220 mg, 70%). The product was kept under nitrogen at−18° C.

Electronic Impact Mass Spectrum M+: 196.

C. Ethyl (3S, 4aR, 6S, 8aR)6-((2-ethoxycarbonyl-5-methylphenyl)thio)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

Following the procedures for Example 22, Step C, decahydroisoquinolinemesylate from preparation 3 (145 mg, 0.40 mmol), potassium carbonatesolid (65 mg, 0.46 mmol, twice) and thiol from step B (90 mg, 0.42 mmol,twice) gave, after flash chromatography (silica gel, hexane-ethylacetate 3:1) the desired product (107 mg, 57% yield)

Electronic Impact Mass Spectrum M+: 463.

D. (3S, 4aR, 6S, 8aR)6-((2-Carboxy-5-methylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures for Example 22, Step D, extensive hydrolysis ofmaterial from step C (54 mg, 0.12 mmol) with 6M hydrochloric acid (3 mL)gave the title product (39 mg, 84% yield).

M.p.>177° C. (dec).

Fast Atom Bombardment Mass Spectrum M-HCl+1: 350.

¹H NMR (CD₃OD, 200.15 MHz): 7.78 (d, J=7.9 Hz, 1H); 7.29 (s, 1H); 7.03(d, J=7.7 Hz, 1H); 4.01 (m, 1H); 3.5-3.2 (m, 2H); 3.09 (br d, J=10.3 Hz,1H); 2.37 (s, 3H); 2.3-1.6 (m, 8H); 1.4 (m, 2H).

EXAMPLE 25 Preparation of (3S, 4aR, 6S, 8aR)6-((2-carboxy-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Ethyl 2-mercapto-4-Chlorobenzoate.

4-Chloro-2-mercaptobenzoic acid (2.9 g, 15.4 mmol) was dissolved inethanol (200 mL) and concentrated sulfuric acid (9 mL) was added. Thesolution was stirred at 80-85° C. overnight. The solvent was evaporatedin vacuo. The residue was dissolved with 200 mL of diethyl ether andwashed with water (100 mL) and sodium bicarbonate saturated solution(2×100 mL). The organic layer was dried, filtered and concentrated invacuo. Flash chromatography (silica gel, 15% ethyl acetate/hexane) gave2.5 g of the title compound (75%).

Electronic Impact Mass Spectrum M+: 216.

B. Ethyl (3S, 4aR, 6S, 8aR)6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To the intermediate from step A (70 mg, 0.32 mmol) a solution of thematerial from preparation 3 (78 mg, 0.21 mmol) in acetone (2 mL) wasadded, followed by addition of anhydrous potassium carbonate solid (50mg, 0.36 mmol). The resulting yellow suspension was stirred under refluxfor 24 h. More anhydrous potassium carbonate (50 mg, 0.36 mmol) and morethiol from step A (70 mg, 0.32 mmol) in acetone (0.5 mL) were added andthe mixture stirred under reflux for 20 h. The reaction was cooled downand quenched with a saturated solution of ammonium chloride (1 mL). Themixture was extracted with ethyl acetate (10 mL) and the organic layerwas dried, filtered and concentrated in vacuo. Flash chromatography(silica gel, 60% diethyl ether/hexane) gave the title compound as an oilin 67% yield.

Electronic Impact Mass Spectrum M+1: 485

C. (3S, 4aR, 6S, 8aR)6((2-Carboxy-5-chlorophenyl)thio)1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

The intermediate from step B (30 mg, 0.06 mmol) was treated with 6Mhydrochloric acid under reflux for 60 h. The solution was cooled downand concentrated in vacuo, followed by washing the resulting solid withacetone (3×5 mL), to give an off-white solid (17 mg, 68%)

Fast Atom Bombardment Mass Spectrum M+1: 370

Analysis calculated for C₁₇H₂₁Cl₂NO₄S.1.5H₂O: C, 47.12; H, 5.58; N,3.23. Found: C, 47.12; H, 5.51; N, 3.39.

EXAMPLE 26 Preparation of (3S, 4aR, 6S, 8aR)6-((2-carboxy-4-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicAcid Hydrochloride

A. Ethyl 5-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate

To a solution of 5-chlorosalicylic acid ethyl ester (500 mg, 2.49 mmol)and 2,6-lutidine (534 mg, 0.58 mL, 4.98 mmol) in dichloromethane at 0°C., trifluoromethanesulfonic anhydride (773 mg, 0.46 mL, 2.74 mmol) wasadded dropwise and the reaction was stirred 6 h at room temperature.More trifluoromethanesulfonic anhydride (0.25 mL) and 2,6-lutidine (1.1mL) were added and the reaction stirred at room temperature overnight.More trifluoromethanesulfonic anhydride (0.35 mL) and 2,6-lutidine (0.40mL) and 4(N,N-dimethylamino)pyridine (44 mg, 0.36 mmol) were added andthe reaction was stirred at room temperature overnight. The reactionmixture was treated with 1.2M hydrochloric acid and the phases wereseparated. The aqueous phase was back-extracted with dichloromethane andthe combined organic phases were washed with brine, dried with anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (silica gel, hexane-ethyl acetate 65:1)to give the triflate as a pale yellow oil (547 mg, 66% yield).

Electronic Impact Mass Spectrum M+: 332.

B. Ethyl 2-mercapto-5-chlorobenzoate

To a solution of the triflate from step A (100 mg, 0.30 mmol) in drytoluene (2 mL) under nitrogen at room temperature, a solution oftetrakistriphenylphosphine palladium (0) (0.10 equiv, 35 mg, 0.03 mmol)and sodium triisopropilsilanethiolate in dry tetrahydrofuran (1.0 equiv,prepared from triisopropilsilanethiol (190 mg, 1.0 mmol) and sodiumhydride (95%, 24 mg, 1.0 mmol) in tetrahydrofuran (2 mL) as in Example22, Step B) was added and the reaction mixture was warmed at 90° C.(bath temp) for 4 h.

The reaction mixture was cooled down and concentrated in vacuo. Flashchromatography (silica gel, hexane-ethyl acetate 40:1) gave 92 mg of amixture of triisopropylsilylarylthiol and free arylthiol contaminatedwith small amounts of triphenylphosphine, which was used without furtherpurification in next step.

Electronic Impact Mass Spectrum M+-triisopropylsilyl: 216

C. Ethyl (3S, 4aR, 6S, 8aR)6-((2-ethoxycarbonyl-4-chlorophenyl)thio)-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of the mixture from step B in N,N-dimethylformamide (0.5mL), tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.12mL, 0.12 mmol) was added and the reaction mixture was stirred for 1 h atroom temperature. A solution of material from preparation 3 (50 mg, 0.13mmol) in N,N-dimethylformamide (0.5 mL) was then added and the resultingmixture was stirred at 60° C. overnight. Ethyl acetate and water wereadded and the phases were separated. The organic phase was washedsucessively with 1.2 M hydrochloric acid, brine, dried (sodium sulfate)and concentrated in vacuo. The residue was purified by flashchromatography (silical gel, hexane-diethyl ether 2:3) to give thedesired product in 17% yield.

Electronic Impact Mass Spectrum M+−3 carboxylates: 279.

D. (3S, 4aR, 6S, 8aR)6-((2-Carboxy-4-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures for Example 22, Step D, thedecahydroisoquinoline derivative from step C (10 mg, 0.021 mmol) gave anoff-white solid (4 mg, 47% yield).

¹H NMR (CD₃OD, 200.15 MHz): 7.84 (br s, 1H); 7.48 (br s, 2H); 4.01 (brd, J=12 Hz, 1H); 3.5-3.0 (m, 3H); 2.3-1.7 (m, 8H); 1.5-1.2 (m, 2H).

Fast Atom Bombardment Mass Spectrum M-HCl+1: 370

EXAMPLE 27 Preparation of Ethyl(3S, 4aR, 6S, 8aR)6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatehydrochloride

Material from Example 25 (1.78 g, 4.39 mmol) was suspended in saturatedhydrogen chloride solution in ethanol (100 mL) and the reaction mixturewas heated at reflux overnight. The solvent was concentrated in vacuo.The solid was triturated with ethyl ether and was filtered to afford1.75 g (86%) of the title compound.

Ion Electrospray Mass Spectrum M-HCl+1: 425

Preparation 4 4-Benzyl-2-fluoro-benzonitrile

A. Trifluoro-methanesulfonic acid 4-cyano-3-fluoro-phenyl Ester

To a solution of 16.0 g (116.6 mmol) of 2-fluoro-4-hydroxybenzonitrileand 50.0 g (140.0 mmol) of N-phenyltrifluoromethanesulfonimide in 250 mLof dichlorormethane is added N,N-diisopropylethylamine and the mixtureis stirred for 16 hr at room temperature. The mixture is then washedwith 10% aqueous sodium bisulfate. The organic portion is separated andthe aqueous portion is extracted three times with dichlorormethane. Thecombined organic portions are dried (Na₂SO₄), filtered and concentratedin vacuo. Chromatography (silica gel, 50% chloroform/hexane) of theresidue affords 26.7 g (85%) of the title compound.

Field Desorption Mass Spectrum: M=269.

B. 4-Benzyl-2-fluoro-benzonitrile

To a room temperature solution of 1.5 g (5.57 mmol) of the triflate fromStep A above, 0.32 g (6.56 mmol) of bis(dibenzylideneacetone)palladiumand 1,1′-bis(diphenylphosphino)-ferrocene in 15 mL of tetrahydrofuran isadded to 12.25 mL (6.13 mmol) of a 0.5 M solution of benzylzinc bromidein tetrahydrofuran via syringe. The mixture is heated to 65° C. for 16hr and cooled to room temperature. The mixture is poured into saturatedammonium chloride and extracted two times with ethyl acetate. Thecombined organic portions are dried (MgSO₄), filtered, and concentratedin vacuo. Chromatography (Biotage, 100% toluene) of the residue affords0.76 g (65%) of the title compound.

Field Desorption Mass Spectrum: M=211.

EXAMPLE 28 (3S, 4aR, 6S, 8aR)6-[5-Benzyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Example 9 using 0.45 g (1.51mmol) of material from Preparation 2 and 0.32 g (1.51 mmol) of materialfrom Preparation 4 affords 0.13 g (21% overall yield) of the titlecompound.

Electrospray Mass Spectrum: M+1=434.

Preparation 5 2-Fluoro-4-thiophen-2-yl-benzonitrile

To a degassed solution of 2.5 g (9.3 mmol) of the triflate fromPreparation 4, Step A above, 1.3 g (10.4 mmol) thiophene and 1.4 g (10.4mmol) of potassium carbonate in 24 mL of toluene is added to 0.4 g (0.37mmol) of tetras (triphenylphosphine) palladium(0). The mixture is heatedto 90° C. for 5.5 hr and cooled to room temperature. The mixture is thendiluted with ethyl acetate and washed with water. The organic portion isseparated and the aqueous portion is extracted two times with ethylacetate. The combined organic portions are dried over MgSO₄, filtered,and concentrated in vacuo. Chromatography (silica gel, 10% ethylacetate/hexane) of the residue affords 1.2 g (79%) of the titlecompound.

Field Desorption Mass Spectrum: M=203.

EXAMPLE 29 (3S, 4aR, 6S, 8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. (3S, 4aR, 6S, 8aR)6-[5-(2-thienyl)-2-cyano]-phenoxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8,a-decahydroisoquinoline-3-carboxilicacid

Following the procedures as described in Step A of Example 9, using 1.0g (3.9 mmol) of (38, 4aR, 68, 8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxilicacid (prepared as described in U.S. Pat. Nos. 4,902,695, 5,446,051, and5,356,902) and a 0.8 g (3.9 mmol) of material from Preparation 5,affords 0.84 g (49%) of the title compound.

Electrospray Mass Spectrum: M+NH₄ ⁺=458.

B. (3S, 4aR, 6S, 8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A solution of 0.84 g (1.9 mmol) of material from Part A and 1.6 g (4.8mmol) of azidotributyltin, in just enough tetrahydrofuran to dissolvethe nitrile, is heated to 95° C. for 48 hr and the tetrahydrofuran isallowed to evaporate from the mixture. The mixture is cooled to roomtemperature and 8 mL of methanol is added. To this mixture is added 0.8mL of 5 N sodium hydroxide and the mixture is stirred for 1.5 hr. Themixture is concentrated in vacuo and partitioned between water anddiethyl ether. The organic portion is separated and the aqueous portionis washed once with diethyl ether. The aqueous portion is acidified(pH2) with 10% aqueous sodium bisulfate and extracted four times withethyl acetate. The combined organic portions are dried (MgSO₄),filtered, and concentrated in vacuo. The resulting solid is suspended inethyl acetate and stirred for 16 hr. The suspension is filtered anddried in vacuo to afford 0.57 g (62%) of the title compound.

Electrospray Mass Spectrum: M+1=484.

C. (3S, 4aR, 6S, 8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To a suspension of 0.56 g (1.32 mmol) of material from Part B in 8 mL ofchloroform is added 0.75 m]L (5.28 mmol) of iodotrimethylsilane. Themixture is stirred for 3 hr and 0.19 mL (1.32 mmol) more ofiodotrimethylsilane is added. The mixture is stirred for 16 hr more andconcentrated in vacuo. Water is added and the mixture is concentrated invacuo two times. The resulting solid is suspended in water, filtered,and rinsed with acetone then diethyl ether. A precipitate forms in thefiltrate and is filtered and dried in vacuo. The solids are combined,suspended in 10 mL of 5 N hydrochloric acid, and stirred for 16 hr. Thesuspension is filtered and rinsed with water, acetone, and then diethylether. The solid is dried in vacuo to afford 0.13 g (21%) of the titlecompound.

Electrospray Mass Spectrum: M+1=426.

Preparation 6 3,2′-Difluoro-biphenyl-4-carbonitrile

The material from Preparation 4, Step A (2.5 gm, 9.3 mmol),2-Fluorophenylboronic acid (1.82 gm, 13.0 mmol), and powdered potassiumcarbonate (1.93 gm, 13.9 mmol) are combined with toluene (25 mL). Thesolution is stirred under a nitrogen atmosphere and degassed.Tetrakis(triphenylphosphine)palladium(0) (1.07 gm, 0.93 mmol) is addedwith a toluene rinse (5 mL), and the solution is degassed and heated at90° C. overnight. The reaction is diluted with ethyl acetate and washedwith distilled water (2×). The separated aqueous layer is back extractedwith ethyl acetate (3×). The combined organics are dried (magnesiumsulfate), filtered, and concentrated to give crude oil (3.14 gm).Chromatography (0 to 50% chloroform in hexane) affords the product as awhite solid: 1.97 μm (98.5%). MS (m/z, EI+): 215.3.

EXAMPLE 30 (3S,4aR,6S,8aR)6-[2′-Fluoro-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. (3S,4aR,6S,8aR)6-(4-Cyano-2′-fluoro-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester

The material from Preparation 6 (0.36 gm, 1.67 mmol) is added to a 0° C.solution of material from Preparation 2 (0.50 gm, 1.67 mmol) andpotassium tert-butoxide (1.0 M in tetrahydrofuran, 5.01 mL) in anhydroustetrahydrofuran (6 nL), after the solution is stirred at 0° C. for 20minutes. The reaction is stirred for 24 hrs at room temperature, andpotassium tert-butoxide (1.0 M in tetrahydrofuran, 0.84 mL) is added at0° C. The reaciton is then stirred at room temperature for a few hours,and then diluted with aqueous sodium bisulfate (10% aq). The separatedaqueous layer is extracted with ethyl acetate (3×). The combinedorganics are dried (magnesium sulfate), filtered, and concentrated invacuo to give crude material (1.10 gm). Chromatography (0-30% ethylacetate in hexane with 2% acetic acid) gives the title product: 0.37 gm(45%). MS (m/z, ES+): 495.2.

B. (3S,4aR,6S,8aR)6-[2′-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To a solution of material from Step A (0.34 gm, 0.69 mmol) in anhydroustetrahydrofuran (0.8 mL) is added azidotributyltin (0.68 gm, 2.05 mmol).The reaction is stirred under nitrogen at 95° C. for 3 days. Thereaction is diluted in a small volume of dichloromethane andchromatographed (40% ethyl acetate in hexane containing 3% acetic acidto give the desired product.

C. (3S,4aR,6S,8aR)6-[2′-Fluoro-4-(2-H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To a solution of material from Step B in ethyl acetate (3.5 mL) is addeda solution of hydrogen chloride (2 M in ethyl acetate, 3.5 mL). Thereaction is stirred at room temperature under nitrogen overnight. Theprecipitated solid is filtered, washed with ethyl acetate (2×) and thenwith diethyl ether (2×), and dried in a vacuum oven to give finalproduct: 0.179 gm (55% combined Steps B&C yield). MS (m/z, ES+): 438.2.

EXAMPLE 31 (3S,4aR,6S,8aR)6-[4′-Methyl-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Preparation 6 and Example 30,above, and using Trifluoro-methanesulfonic acid 4-cyano-3-fluoro-phenylester (0.64 gm, 2.37 mmol) and 4-Methylphenylboronic acid (0.45 gm, 3.33mmol) affords 0.301 gm (38% overall yield) of the title compound. MS(m/z, ES+): 434.2.

EXAMPLE 32 (3S,4aR,6S,8aR)6-[5-Naphthalen-2-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Preparation 6 and Example 30,above, and using Trifluoro-methanesulfonic acid 4-cyano-3-fluoro-phenylester (0.55 gm, 2.04 mmol) and 2-Naphthaleneboronic acid (0.49 gm, 2.86mmol) affords 0.069 μm (6.6% overall yield) of the title compound. MS(m/z, ES+): 470.3

EXAMPLE 33 (3S,4aR,6S,8aR)6-[2′-Methoxy-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Following the procedures as described in Preparation 6 and Example 30,Step A, above, and using Trifluoro-methanesulfonic acid4-cyano-3-fluoro-phenyl ester (0.59 gm, 2.2 mmol) and2-Methoxyphenylboronic acid (0.47 gm, 3.1 mmol) affords 0.41 gm (45%yield) of the N-boc protected title compound. MS (m/z, ES+): 470.3 Thefinal title product is isolated by the procedures described in Example30, Step B.

MS (m/z, ES+): 450.2

Preparation 7 2-Hydroxy-4-pyrazol-yl-benzonitrile

A. Preparation of 2-Benzyloxy-4-fluoro-benzonitrile

To 2.5 mL benzyl alcohol in 80 mL THF is added 1.87 g NaH. After onehour stirring at room temperature, 5.0 g of 2,4-Difluorobenzonitrile isadded. After stirring one hour, the reaction is quenched with excesswater and concentrated in vacuo. The residue is redissolved in ethylacetate and washed with water, brine, dried over sodium sulfate,filtered and concentrated in vacuo. The product is recrystallizde incarbon tetrachloride to give 3.24 g (39.7%) of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 7.6-7.55 (dd, 1H), 7.5-7.32 (m, 5H), 6.78-6.7(m, 2H), 5.2 (s, 2H).

B. Preparation of 2-Benzyloxy-4-pyrazol-1-yl-benzonitrile

To 0.180 g pyrazole in 5 mL DMF is added 0.105 g NaH. After stirring 50minutes at room temperature, 0.200 g of the material from Step A, above,is added all at once with 5 mL DMP. After 2 hours at room temperature,the reaction is quenched with water and Concentrated in vacuo. Theresidue is redissolved in ethyl acetate and washed with water, brine,dried over sodium sulfate, filtered and concentrated in vacuo. Flashchromatography eluting with toluene provides 0.181 g (74.8%) of thetitle compound.

¹H NMR (400 MHz, CDCl₃) δ 7.92 (s, 1H), 7.75 (s, 1H), 7.67-7.65 (d, 1H),7.6 (s, 1H), 7.52-7.47 (d, 2H), 7.45-7.4 (t, 2H), 7.4-7.34 (d, 1H),7.25-7.2 (d, 1H), 6.55 (s, 1H), 5.3 (s, 2H).

C. Preparation of 2-Hydroxy-4-pyrazol-1-yl-benzonitrile

To 0.395 g of the material from Step B, above, dissolved in 10 mL THF,is added a catalytic amount of 10% Pd/C and excess ammonium formate. Thereaction is heated to 50° C. for 45 minutes. Upon cooling, celite isadded. The reaction is then gravity filtered and concentrated in vacuo.The residue is redissolved in ethyl acetate and washed with water,brine, dried over sodium sulfate, filtered and concentrated in vacuo togive 0.152 g of the final title compound (57.1%).

¹H NMR (400 MHz, DMSO-d) δ 8.35 (s, 1H), 7.75 (s, 1H), 7.61-7.59 (d,1H), 7.4 (s, 1H), 7.35-7.3 (d, 1H), 6.55 (s, 1H).

EXAMPLE 34 (3S, 4aR, 6S, 8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. Preparation of (3S, 4,8aR)6-8aR-(2-Cyan(5-pyrazol-1-yl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester

To 0.145 g of the material from Preparation 7, 0.256 g of Ethyl (3S,4aR, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate(prepared essentially as described in Preparation 1), and 0.308 gtriphenylphosphine are added to 0.18 mL diethylazodicarboxylate. Afterstirring at room temperature overnight, the reaction is concentrated invacuo. Flash chromatography eluting with a stepwise gradient from 5-25%Ethyl acetate/toluene provides 0.226 g of the title compound (58.4%yield).

¹H NMR (400 MHz, CDCl₃) δ 7.9 (m, 1H), 7.8 (m, 1H), 7.7-7.6 (dd, 1H),7.4 (m, 1H), 7.25-7.18 (m, 1H), 7.18-7.1 (d, 1H), 6.5-6.4 (m, 1H),4.95-4.65 (m, 2H), 4.2-4.05 (m, 2H), 3.9-3.7 (m, 1H), 3.25-3.0 (m, 1H),2.75-2.5 (m, 1H), 2.17-2.07 (d, 1H), 2.07-1.9 (m, 3H), 1.9-1.75 (m, 2H),1.75-1.55 (m, 2H), 1.45-1.3 (m, 9H), 1.3-1.15 (m, 3H). MS m/z: 395.3(m⁺-99).

B. (35, 4aR, 6S, 8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3 ethyl ester

To 0.220 g of the material from Step A, above, is added 0.5 mLazidotributyltin and 0.5 mL toluene. The reaction is heated to 90° C.for two days. The residue is dissolved in ethyl acetate and washed withwater, brine, dried over sodium sulfate, filtered and concentrated invacuo. Flash chromatography eluting with 2% MeOH/CHCl₃ provides 0.142 gof the title compound (59.4% yield).

¹H NMR (400 MHz, d-MeOH) δ 8.35 (s, 1H), 7.81-7.79 (d, 1H), 7.73 (s,1H), 7.61 (s, 1H), 7.5-7.46 (d, 1H), 6.55 (s, 1H), 4.954.89 (bm, 1H),4.454.29 (bm, 1H), 4.15-4.03 (q, 2H), 3.75-3.65 (d, 1H), 3.1-2.9 (bm,1H), 2.25-2.15 (d, 1H), 2.0-1.92 (d, 1H), 1.85-1.53 (m, 6H), 1.43 (s,9H), 1.38-1.1 (m, 4H), 0.92-0.84 (t, 1H).

C. (3S, 4aR, 6S, 8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester

To 0.129 g of the material from Step B, above, dissolved in 10 mL MeOHis added 0.72 mL 1N NaOH. The reaction is heated to 50° C. overnight.0.72 mL 1N NaOH is then added and heated for four more hours. Uponcompletion, the reaction is concentrated in vacuo, redissolved in waterand acidified to pH 3, extracted with ethyl acetate, washed with brine,dried over sodium sulfate, filtered and concentrated in vacuo. Flashchromatography eluting with 10% MeOH/CHCl₃ provides 0.040 g of the titlecompound (32.8% yield), which is used directly in the following step.

D. (3S, 4aR, 65, 8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

To 0.040 g of the material from Step C, above, dissolved in 5 mL CH₂Cl₂,is added 3 mL 2M HCl in diethyl ether. After stirring four hours atambient temperature, the reaction is concentrated in vacuo.

¹H NMR (400 d-MeOH) δ 8.4 (s, 1H), 8.06-8.04 (d, 1H), 7.78 (s, 1H), 7.72(s, 1H), 7.52-7.49 (d, 1H), 6.58 (s, 1H), 4.75-4.65 (1 μm, 1H—),4.05-3.96 (d, 1H), 3.16-3.08 (dd, 1H), 2.33-1.88 (m, 10H), 1.66-1.5 (m,1H).

MS m/z: 410.2 (m⁺+1).

Preparation 8 2-Hydroxy-4-indol-yl-benzonitrile

A. Preparation of 2-Benzyloxy-4-indol-1-yl-benzonitrile

Using indole, the title compound is prepared according to the proceduresdescribed in Preparation 7, step B and provides 0.39 g (91.1% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.73-7.63 (m, 2H), 7.6-7.37 (m, 5H), 7.3-7.07(m, 6H), 6.71-6.68 (d, 1H, 5.3 (s, 2H).

B. Preparation of 2-Hydroxy-4-indol-1-yl-benzonitrile

Using the material from Step A, above, the title compound is preparedaccording to the procedures described in Preparation 7, step C andprovides.188 g (66.7% yield).

¹H NMR (400 z, CDCl₃) δ 7.65-7.54 (m, 3H), 7.27-7.1 (m, 5H), 6.67 (d,1H).

EXAMPLE 35 (3S, 4aR, 6S, 8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

A. (3S, 4aR, 6S, 8aR)6-(2-Cyano-5-indol-1-yl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester

Using the material from Preparation 8, above, the title compound isprepared according to the procedures described in Example 34, step A andprovides 0.233 g (53.4% yield).

MS m/z: 444.3 (m⁺−99).

B. (3S, 4aR, 6S, 8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester

Using the material from Step A, above, the title compound is preparedaccording to the procedures described in Example 34, step B and provides0.19 g (76% yield).

MS m/z: 585.2 (M⁻−1).

C. (3S, 4aR, 6S, 8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester

Using the material from Step B, above, the title compound was preparedaccording to the procedures described in Example 34, step C and provides0.100 g (58.5% yield).

MS m/z: 557.3 (M⁻−1).

D. (3S, 4aR, 6S, 8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

Using the material from Step C, above, the title compound is preparedaccording to the procedures described in Example 34, step D and provides0.078 g (92.9% yield).

¹H NMR (400 MHz,d-MeOH) δ 8.14-8.11 (d, 1H), 7.64-7.6 (d, 2H), 7.55 (s,1H), 7.43 (s, 1H), 7.37-7.35 (d, 1H), 7.22-7.18 (t, 1H), 7.15-7.1 (t,1H), 6.7 (s, 1H), 4.74-4.64 (m, 1H), 4.03-4.0 (d, 1H), 3.37-3.3 (t, 1H),3.15-3.1 (dd, 1H), 2.18-1.93 (m, 5H), 1.85-1.68 (m, 3H), 1.68-1.55 (m,2H). MS m/z: 459.2 (m⁺+1).

Preparation 9 2-Hydroxy-4-pyrrol-1-yl-benzonitrile

A. Preparation of 2-Benzyloxy-4-pyrrol-1-yl-b benzonitrile

Using pyrrole, the title compound is prepared according to theprocedures described in Preparation 7, step B and provides 0.457 g(94.6% yield).

¹H NMR (400 MHz, CDCl₃) δ 7.57-7.56 (d, 1H), 7.6-7.44 (d, 2H), 74-7.35(t, 2H), 7.34-7.3 (d, 1H), 7.01-6.98 (m, 3H), 6.94 (s, 1H), 6.34 (s,2H), 5.23 (s, 2H).

B. Preparation of 2-Hydroxy-4-pyrrol-1-yl-benzonitrile

Using the material from Step A, above, the title compound is preparedaccording to the procedures described in Preparation 7, step C andprovides.213 g (70.5% yield).

¹H NMR (400 z,d-MeOH) δ 7.54-7.51 (d, 1H), 7.7 (s, 2H), 7.05-7.02 (d,1H), 6.96 (s, 1H), 6.28 (s, 2H).

EXAMPLE 36 (3S, 4aR, 6S, 8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

A. (3S, 4aR, 6S, 8aR)6-(2-Cyano-5-pyrrol-1-yl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester

Using the material from Preparation 9, above, the title compound isprepared according to the procedures described in Example 34, step A andprovides 0.216 g (38% yield).

MS m/z: 394.2 (M⁺−99).

B. (3S, 4aR, 6S, 8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester 3-ethyl ester

Using the material from Step A, above, the title compound is preparedaccording to the procedures described in Example 34, step B and provides0.074 g (35% yield) which is used directly in the following step.

C. (3S, 4aR, 6S, 8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-2,3-dicarboxylicacid 2-tert-butyl ester

Using the material from Step B, above, the title compound is preparedaccording to the procedures described in Example 34, step C andprovides.014 g, (22.6% yield) which is used directly in the followingstep.

D. (3S, 4aR, 6S, 8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid hydrochloride

Using the material from Step C, above, the title compound is preparedaccording to the procedures described in Example 34, step D. andprovides 0.012 g (97.5% yield).

¹H NMR (400 MHz,d-MeOH) δ 8.0-7.98 (d, 1H), 7.35-7.3 (d, 3H), 7.3-7.24(d, 1H), 6.32 (s, 2H), 4.78-4.69 (m, 1H), 4.0-3.96 (dd, 1H), 3.37-3.3(t, 1H), 3.14-3.08 (dd, 1H), 2.33-2.25 (m, 1H), 2.2-1.74 (m, 7H),1.64-1.5 (m, 1H), 1.26 (s, 1H).

MS m/z: 409.3 M⁺+1), 407.3 (M⁻−1).

Preparation 10 (3S, 4aR, 6S, 8aR)6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

To a slurry of 17.3 g of (3S, 4aR, 8aR)6-oxo-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid (46 mmol) in 240 mL of tetrahydrofuran is added 106 mL if 1.0 ML-Selectride in tetrahydrofuran. The mixture is stirred for 1 hour atroom temperature, then quenched with 130 mL of 1.4 M hydrochloric acid.The layers are separated and the aqueous phase extracted with 50 mL oftert-butyl methyl ether. The organic phases are combined and extractedwith 75 mL of saturated aqueous sodium carbonate. The aqueous phase iswashed twice with 30 mL portions of tert-butyl methyl ether thenacidified to pH 1 with 6 M hydrochloric acid. The product is extractedinto 75 mL of tert-butyl methyl ether. The organic mixture is dried withsodium sulfate, and concentrated to 8.17 g of yellow solid. The productis crystallized from 20 mL of tert-butyl methyl ether to provide 6.92 gof the title compound (59% yield).

Preparation 11 6-Chloro-2-fluoro-benzotetrazole

To a 12L round bottomed flask under nitrogen was added trimethylaluminum (1930 mL of a 2M solution in toluene, 3.86 mol). The flask iscooled to −7° C. before adding azidotrimethylsilane (512.5 mL, 3.86 mol)via canula such that the internal temperature is maintained at less than3° C. To this flask is added 6-chloro-2-fluorobenzonitrile (500 g, 3.21mol) dropwise as a solution in toluene (1L). The reaction is slowlywarmed to room temperature then heated to 90° C. A cold finger is usedto condense tetramethylsilane as it boiled from the reaction mixture.The reaction is heated at 90° C. for 13 hours before cooling to roomtemperature. The reaction is cooed to 0° C. with an ice bath thentransferred slowly via cannula to a pre-cooled (−5° C.) solution of 6Naqueous HCl (3L) and ethyl acetate (3L). The internal temperature duringthe quench is kept at less than 5° C. After addition, the flask isallowed to warm to room temperature. The reaction is diluted with ethylacetate (2 L) to disolve solids before tranferring to a 22L flask. Thelayers are separated and the aqueous layer was extracted with ethylacetate (1L). The combined organic layers are washed with brine (2L),dried over anhydrous sodium sulfate, and concentrated. 636.4 g. of thetitle compound is obtained (93% yield). Analysis by HPLC and ¹H NMRanalysis shows the purity as greater than 98%.

Preparation 12

To a thick slurry of the material from Preparation 11, above, (101.8 g,0.513 mol) and 4,4′-dimethoxybezhydrol (125 g, 0.513 mol) in 510 mLglacial acetic acid is added concentrated sulfuric acid (5.5 mL). Uponaddition, the reaction immediately becomes red and homogeneous. The redcolor rapidly lightens to orange over several minutes. An endotherm of3-4° C. is also observed as the reaction becomes homogeneous. Afterapproximately 15 minutes, the product begins to crystallize from thereaction mixture resulting in a mild exotherm (<10° C.). After 1 hour,the solid is isolated by filtration and washed with water (1L) thenisopropyl alcohol (0.5 L). The resulting white solid is dried in vacuoat 50° C. to afford 199.8 g of the title compound (91% yield).

EXAMPLE 37 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatepara-toluenesulfonate

p-toluenesulfonic acidA. Preparation of

To a slurry of sodium hydride (60% dispersion in mineral oil, 2.94 g,73.5 mmol) in dry dimethyl sulfoxide (25 mL) is added the material fromPreparation 10 (9.44 g, 36.7 mmol) dropwise as a solution in dimethylsulfoxide (21 mL). During the course of the addition (40 min.), acooling bath is used to maintain the temperature at or below 25° C.After stirring 15 minutes at ambient temperature, the material fromPreparation 12 (10.4 g, 24.5 mmol) is added in one portion as a solid.The slurry is stirred at room temperature for 20 minutes before heatingto 40° C. for 2.75 hours. Analysis of the reaction mixture by HPLC showsno additional progress after this point and the reaction is cooled toroom temperature. The reaction is quenched by addition of 1N aqueoushydrogen chloride solution (50 mL), water (200 mL) and ethyl actetate(200 mL). The layers are separated and the aqueous layer is extractedwith ethyl acetate (1×50 mL). The combined organic layers are washedwith water (2×100 mL) and 10% aqueous sodium chloride solution (1×10mL). The organic layer is then dried over anhydrous sodium sulfate andconcentrated in vacuo to afford a crude oil. The crude product ispurified on silica gel eluting 1% methanol in methylene chloridefollowed by 5% methanol in methylene chloride to afford 11.84 g. of thetitle compound (73% yield) as a white foam.B. Preparation of

To a solution material from Step A, of the above (16.87 g, 25.4 mmol),in N,N-dimethylformamide (170 mL) is added powder potassium carbonate(4.55 g, 33 mmol) and 3-(bromomethyl)pentane (4.62 mL, 33 mmol). Thereaction mixture is heated to 80° C. under nitrogen. After 1 h, analysisby thin layer chromatography and HPLC indicates that the reaction wascomplete. The reaction is cooled and diluted with water (500 mL) andmethylene chloride (170 mL). The organic layer is washed with brine,dried over anhydrous magnesium sulfate, and concentrated in vacuo toafford 17.8 g. of the title compound (94% yield) as a foam.

C. 2-Ethyl-butyl (3S, 4aR, 65, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

To a solution of the material from Step B, above (216 g, 289 mmol), isadded anisole (94.4 mL, 868.3 mmol) and trifluoroacetic acid (564 mL).The dark red solution is stirred at RT until complete conversion isobserved by HPLC (6.5 h). The reaction is concentrated to a dark redoil. The residual trifluoroacetic acid is removed by azeotropicdistillation with chloroform. The resulting oil is dissolved inmethylene chloride (800 mL) and washed with pH 4 buffer (4×1L). Theorganic layer is dried over anhydrous magnesium sulfate, filtered, andconcentrated to a crude oil. The product is purified on silica gel (2Kg) eluting methylene chloride, 10% ethyl acetate in methylene chloride,then ethyl acetate. The appropriate fractions are concentrated in vacuoto provide 132 g. of the title compound as a white foam (88% yield).

D. 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

The material from Step C, above (390 g, 750 mmol) and 187 mL oftrimethylsilyliodide are combined in 1.65 L of dichloromethane and themixture stirred at ambient temperature for 24 hours. At this time themixture is quenched with 10 mL of saturated aqueous sodiumhydrogencarbonate and combined with 325 mL of tetrahydrofuran. Thereaction is further quenched with a total of 2.0 L of saturated aqueoussodium hydrogencarbonate. The mixture is stirred for 1 hour and theproduct is isolated by filtration. The solids are washed with water anddichloromethane then dried in vacuo to provide 230 g of the titlecompound.

The isolated solids are further purified by recrystallization. A mixtureof 245 g of the title compound is combined with 2.0 L of water and 200mL of acetonitrile. The mixture is adjusted to pH 6.8 by the addition of1.0 M hydrochloric acid. An additional 1.0 L of acetonitrile is addedand the mixture is heated to effect a solution. The solution is allowedto cool to ambient temperature producing a precipitate. After themixture cools to approximately 25° C. for 20 minutes the solids arecollected by filtration. The solids are washed with water and dried invacuo to provide 211 g of the title compound.

E. 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatepara-toluenesulfonate

To a suspension of the material from Step D, above (211 g, 457 mmol) in1100 mL of 2-propanol, is added p-toluenesulfonic acid monohydrate (91.7g, 480 mmol). The mixture is heated to 55° C. to effect a solution thenallowed to cool to ambient temperature for 2 hours and then furthercooled to approximately 3° C. for 90 minutes. The solids are collectedby filtration and washed with 500 mL of cold 2-propanol. The solids aredried in vacuo to provide 270 g (93% yield) of the final title compoundas a white powder.

¹H NMR, 500 MHz dmso-d6, 9.23 (bs, 1H), 8.94 (bs, 1H), 7.56 (t, 1H),7.45 (d, 2H), 7.30 (d, 1H), 7.24 (d, 1H), 7.09 (d, 2H), 4.37 (m, 1H),4.17 (m, 1H), 4.13 (dd, 1H), 4.03 (dd, 1H), 3.04 (m, 1H), 2.94 (m, 1H),2.26 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1H), 1.84 (m, 2H), 1.75 (m, 2H),1.60 (m, 3H), 1.48 (m, 1H), 1.29 (m, 4H), 1.09 (m, 1H), 0.83 (t, 6H)

Mp=204° C.

EXAMPLE 38 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatepara-toluenesulfonate

A. (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-2-methoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid

The material from Preparation 10 (20.0 g, 77.7 mmol) is added to 311 mLof 1 M potassium tert-butoxide in tetrahydrofuran followed by theaddition of 6-Chloro-2-fluoro benzotetrazole (Preparation 11) (17.0 g,85.7 mmol). The mixture is heated to 63° C. and monitored forconsumption of the aryl tetrazole by HPLC. After 4 hours the reaction iscooled to 20° C. and quenched by the addition of trimethylsilyl chloride(16.9 g, 155.5 mmol). followed by heating to reflux for 30 minutes. Thereaction mixture is again cooled to ambient temperature and furtherquenched by the addition of 224 mL of 1.5 M hydrochloric acid. Theorganic phase is washed with two 50 mL portions of saturated aqueoussodium chloride. The organic phase is then exchanged for ethyl acetateby atmospheric distillation of the tetrahydrofuran with concurrentaddition of ethyl acetate until the distillation temperature reaches 75°C. The exchange of solvents effects the precipitation of the desiredproduct. The mixture is cooled to 10° C. and the solids are collected byfiltration, washed with ethyl acetate, and dried to provide 43.4 g ofproduct as a white solid.

B. (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid•hydrochloride

To a solution prepared from 85% potassium hydroxide (21.2 g 321 mmol)and 100 mL of water is added the material from Step A, above (20.0 g,45.9 mmol). The solution is heated to 103° C. for 26 hours at which timethe HPLC analysis shows less than 4% starting material remains. Thereaction is cooled to 30° C. and is added over 20 minutes- to 62 mL of 6M hydrochloric acid effecting the precipitation of the desired product.The mixture is cooled to 10° C. and the product is collected byfiltration, washed with 1 M hydrochloric acid, followed by a wash withacetonitrile. The product is dried in vacuo to provide 17 g of the titlecompound (89% yield) as a white solid.

The title compound (20.0 g) is then combined with 200 mL of water andheated to 90° C. to effect a solution. The solution is cooled to 60° C.and 40 mL of 6 M hydrochloric acid is added effecting the precipitationof the title compound. The mixture is stirred at 60° C. for 45 minutesthen cooled to ambient temperature. The recrystallized hydrate productis collected by filtration and washed with 100 mL of acetonitrile. Theproduct was dried in vacuo to 17 g of 2049266 as a white solid and usedin the next step

C. 2-Ethyl-butyl (3S, 4aR, 6S, 8aR)6-[3-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylatepara-toluenesulfonate

A mixture of the hydrate from Step B, above(30.0 g, 69.4 mmol),para-toluenesulfonic acid monohydrate (15.84 g, 83.3 mmol), 75.0 mL of2-ethyl-1-butanol, and 6.0 mL of water is heated to 140° C. over a twohour period. During the heating process, a distillate is collected whichcontains 11 mL of aqueous and 14 mL of organic phases. The mixture iscooled 70° C. and 75 mL of 2-propanol is added. The mixture is furthercooled to 50° C. and 150 mL of tert-butyl methyl ether is added over 20minutes effecting the precipitation of the product. The mixture is thencooled to ambient temperature. The solids are collected by filtration,washed with 50 mL of tert-butyl methyl ether, and dried in-vacuo toprovide 39.0 g (88.6% yield) of the final title compound as a whitesolid.

A suspension of 10.0 g of the product, in a mixture of 49.0 mL of2-propanol and 1.0 mL of water, was heated to solution. The solution isallowed to cool to ambient temperature effecting crystallization. Themixture is stirred for 1 hour at less than 29° C. and then the solidsare collected by filtration. The solids are washed with 7 mL of2-propanol and dried in-vacuo to provide 8.73 g of the recrystallizedtitle compound.

¹H NMR, 500 MHz dmso-d6, 9.23 (bs, 1H), 8.94 (bs, 1H), 7.56 (t, 1H),7.45 (d, 2H), 7.30 (d, 1H), 7.24 (d, 1H), 7.09 (d, 2H), 4.37 (m, 1H),4.17 (m, 1H), 4.13 (dd, 1H), 4.03 (dd, 1H), 3.04 (m, 1H), 2.94 (m, 1H),2.26 (s, 3H), 2.07 (m, 1H), 1.96 (m, 1H), 1.84 (m, 2H), 1.75 (m, 2H),1.60 (m, 3H), 1.48 (m, 1H), 1.29 (m, 4H), 1.09 (m, 1H), 0.83 (t, 6H).

Mp=204° C.

EXAMPLE 39

To establish that the iGluR₅ receptor subtype is mediating apharmacological response in a neurological disease or disorder, thebinding affinity of the panel compounds to the iGluR₅ receptor is firstmeasured using standard methods. For example, the activity of compoundsacting at the iGluR₅ receptor can be determined by radiolabelled ligandbinding studies at the cloned and expressed human iGluR₅ receptor(Korczak et al., 1994, Recept. Channels 3; 41-49), and by whole cellvoltage clamp electrophysiological recordings of currents in acutelyisolated rat dorsal root ganglion neurons (Bleakman et al., 1996, Mol.Pharmacol. 49; 581-585). The selectivity of compounds acting at theiGluR₅ receptor subtype can then be determined by comparing antagonistactivity at the iGluR₅ receptor with antagonist activity at other AMPAand kainate receptors. Methods useful for such comparison studiesinclude: receptor-ligand binding studies and whole-cell voltage clampelectrophysiological recordings of functional activity at human GluR₁,GluR₂,GluR₃ and GluR₄ receptors (Fletcher et al., 1995, Recept. Channels3; 21-31); receptor-ligand binding studies and whole-cell voltage clampelectrophysiological recordings of functional activity at human GluR₆receptors (Hoo et al., Recept. Channels 2;327-338); and whole-cellvoltage clamp electrophysiological recordings of functional activity atAMPA receptors in acutely isolated cerebellar Purkinje neurons (Bleakmanet al., 1996, Mol. Pharmacol. 49; 581-585) and other tissues expressingAMPA receptors (Fletcher and Lodge, 1996, Pharmacol. Ther. 70; 65-89).

iGluR5 Antagonist Binding Affinity Profiles

Cell lines (HEK293 cells) stably transfected with human iGluR receptorsare employed. Displacement of ³ [H] AMPA by increasing concentrations ofantagonist is measured on iGluR₁, iGluR₂, iGluR₃, and iGluR₄ expressingcells, while displacement of 3[H] kainate (KA) is measured on iGluR₅,iGluR₆, iGluR₇, and KA2-expressing cells. Estimated antagonist bindingactivity (K_(i)) in μM, for example, is determined for Compounds ofFormula I. As an indicia of selectivity, the ratio of binding affinityto the iGluR₂ AMPA receptor subtype, versus the binding affinity toiGluR₅ kainate receptor subtype (K_(i) at iGluR₂/K_(i) at iGluR5) isalso determined. The iGluR5 receptor antagonist compounds, as providedby the present invention, provide a K_(i) at the iGluR₅ receptor subtypeof less than 5000 μM, preferably less than 500 μM, even more preferablyless than 50 μM, and most preferably less than 5 μM. The preferredselective iGluR5 receptor antagonists compounds, as provided by thepresent invention, display a greater binding affinity (lower K_(i)) foriGluR₅ than that for iGluR₂, preferably at least 10 fold greater foriGluR₅ than that for iGluR₂, and even more preferably at least 100 fold,and most preferably at least 1000 fold. than that for iGluR₂.

EXAMPLE 40

The following animal model may be employed to determine the ability ofeach of the compounds of Formula I to inhibit protein extravasation, anexemplary functional assay of the neuronal mechanism of migraine.

Animal Model of Dural Protein Extravasation

Harlan Sprague-Dawley rats (225-325 g) or guinea pigs from Charles RiverLaboratories (225-325 g) are anesthetized with sodium pentobarbitalintraperitoneally (65 mg/kg or 45 mg/kg respectively) and placed in astereotaxic frame (David Kopf Instruments) with the incisor bar set at−3.5 mm for rats or 4.0 mm for guinea pigs. Following a midline sagitalscalp incision, two pairs of bilateral holes are drilled through theskull (6 mm posterially, 2.0 and 4.0 mm laterally in rats; 4 mmposteriorly and 3.2 and 5.2 mm laterally in guinea pigs, all coordinatesreferenced to bregma). Pairs of stainless steel stimulating electrodes,insulated except at the tips (Rhodes Medical Systems, Inc.), are loweredthrough the holes in both hemispheres to a depth of 9 mm (rats) or 10.5mm (guinea pigs) from dura.

The femoral vein is exposed and a dose of the test compound is injectedintravenously (i.v.) at a dosing volume of 1 ml/Kg or, in thealternative, test compound is administered orally (p.o) via gavage at avolume of 2.0 ml/Kg. Approximately 7 minutes post i.v. injection, a 50mg/Kg dose of Evans Blue, a fluorescent dye, is also injectedintravenously. The Evans Blue complexes with proteins in the blood andfunctions as a marker for protein extravasation. Exactly 10 minutespost-injection of the test compound, the left trigeminal ganglion isstimulated for 3 minutes at a current intensity of 1.0 mA (5 Hz, 4 msecduration) with a Model 273 potentiostat/galvanostat (EG&G PrincetonApplied Research).

Fifteen minutes following stimulation, the animals are euthanized byexsanguination with 20 mL of saline. The top of the skull is removed tofacilitate the collection of the dural membranes. The membrane samplesare removed from both hemispheres, rinsed with water, and spread flat onmicroscopic slides. Once dried, the tissues are coverslipped with a 70%glycerol/water solution.

A fluorescence microscope (Zeiss) equipped with a grating monchromatorand a spectrophotometer is used to quantify the amount of Evans Blue dyein each sample. An excitation wavelength of approximately 535 nm isutilized and the emission intensity at 600 nm is determined. Themicroscope is equipped with a motorized stage and also interfaced with apersonal computer. This facilitates the computer-controlled movement ofthe stage with fluorescence measurements at 25 points (500 mm steps) oneach dural sample. The mean and standard deviation of the measurementsare determined by the computer.

The extravasation induced by the electrical stimulation of thetrigeminal ganglion has an ipsilateral effect (i.e. occurs only on theside of the dura in which the trigeminal ganglion was stimulated). Thisallows the other (unstimulated) half of the dura to be used as acontrol. The ratio (“extravasation ratio”) of the amount ofextravasation in the dura from the stimulated side, over the amount ofextravasation in the unstimulated side, is calculated. Control animalsdosed with only with saline, yield an extravasation ratio ofapproximately 2.0 in rats and apprximately 1.8 in guinea pigs. Incontrast, a compound which completely prevents the extravasation in thedura from the stimulated side would yield a ratio of approximately 1.0.

Dose-response curves are generated for each of the compounds of FormulaI and the dose that inhibits the extravasation by 50% (ID₅₀) or 100%(ID₁₀₀) is approximated.

EXAMPLE 41

To demonstrate the utility of compounds of the present invention totreat pain or provide analgesic effects, several well known animalmodels may be employed. For example, international application WO98/45270 describes the well known Formalin Test, which is describedbelow:

Formalin Test

For example, male Sprague-Dawley rats (200-250 g; Charles River,Portage, Md.) are housed in group cages and maintained in a constanttemperature and a 12 hour light/12 hour dark cycle 4-7 days beforestudies are performed. Animals have free access to food and water at alltimes prior to the day of the experiment.

Drugs or vehicles are administered intraperitoneally (i.p.) or orally(p.o.) by gavage in a volume of about 1 ml/kg. The test is performed incustom made Plexiglas® boxes about 25×25×20 cm in size (according toShibata et al., Pain 38;347-352, 1989, Wheeler-Aceto et al., Pain, 40;229-238,1990). A mirror placed at the back of the cage allows theunhindered observation of the formalin injected paw. Rats are acclimatedindividually in the cubicles at least 1 hour prior to the experiment.All testing is conducted between, for example, 08:00 and 14:00 h and thetesting room temperature is maintained at about 21-23° C.

Test compounds are administered about 30 minutes prior to the formalininjection. Formalin (50 micoliters of a 5% solution in saline) isinjected subcutaneously into the dorsal lateral surface of the righthind paw with a 27 gauge needle. Observation is started immediatelyafter the formalin injection. Formalin-induced pain is quantified byrecording, for example, in 5 minute intervals, the number of formalininjected pawlicking events and the number of seconds each licking eventlasts. These recordings are made for about 50 minutes after the formalininjection.

Several different scoring parameters have been reported for the formalintest. The total time spent licking and biting the injected paw isdemonstrated to be most relevant (Coderre et al., Eur. J. Neurosci. 6;1328-1334, 1993; Abbott et al., Pain, 60; 91-102, 1995) and may bechosen for the testing score. The early phase score is the sum of timespent licking, in seconds, from time 0 to 5 minutes. The late phase isscored in 5-minute blocks from 15 minutes to 40 minutes and is expressedaccordingly or also by adding the total number of seconds spent lickingfrom minute 15 to minute 40 of the observation period.

Data may be presented as means with standard errors of means (±SEM).Data may also be evaluated by one-way analysis of variance (ANOVA) andthe appropriate contrasts analyzed by Dunnett “t” test for two sidedcomparisons. Differences are considered to be significant if, forexample, the P-value is less than 0.05. Statistics may be determined atthe 5 minute time point and at 5 minute intervals between 15 and 40minutes. Where data are expressed as total amount of time spent lickingin the late phase, statistics may be performed on the total time spentlicking as well and may be indicated accordingly.

In addition to the Formalin Test, the well known Mouse Writhing Test,essentially as described in published International Application WO00/028980, may also be employed to demonstrate the analgesic propertiesof compounds of the present invention.

Mouse Writhing Test

An accepted procedure for detecting and comparing the analgesic activityof different classes of analgesic drugs, for which there is a goodcorrelation with human analgesic activity, is the prevention of aceticacid-induced writhing in mice. Mice are orally administered variousdoses of a test compound or placebo prior to testing. The mice are theninjected intraperitoneally with acetic acid (0.55% solution, 10 mLg)five minutes prior to a designated observation period. Inhibition ofwrithing behavior is demonstrative of analgesic activity. Haubrich etal., “Pharmacology of pravadoline: a new analgesic agent”, The Journalof Pharmacology and Experimental Therapeutics, 255 (1990) 511-522. Forscoring purposes “writhe” is indicated by whole body stretching orcontracting of the abdomen during an observation period beginning aboutfive minutes after receiving the acetic acid.

ED₅₀ values, and their standard error of means (SEM), are determinedusing accepted numerical methods for all test compounds administered.For example, see R. E. Kirk (1982) “Experimental Design: Procedures forthe behavioral sciences,” 2nd ed. One method to establish thesignificance of the analgesic activity of a given test compound comparedto that of another is to calculate the SEM values for each ED₅₀ value.If the SEM values do not overlap the line of addition, then the ED₅₀values are significantly different from the line of addition.

Yet another accepted animal model to demonstrate the ability of aparticular compound to treat pain, or provide analgesic effects, is thewell known Rat Model of Carrageenan-induced Thermal Hyperalgesia, alsodescribed in published International Application WO 00/028980.

Carrageenan-induced Thermal Hyperalgesia in Rats

Another accepted method for detecting and comparing the analgesicactivity of different classes of analgesic compounds for which there isgood correlation with human analgesic activity is the reversal ofcarrageenan-induced thermal hyperalgesia in rats (Hargreaves et al. Pain32:77-88, 1988).

Rats are administered a dose test compound or vehicle and then injectedsubcutaneously into one hindpaw, with carrageenan (1.5% w/v, 100 μl).The response to noxious thermal stimulus is determined two hours laterusing a commercially available thermal plantar device (Ugo Basil, Italy)according to established methods (Hargreaves et al. Pain 32:77-88,1988). Briefly, animals are habituated to a plastic behavioral enclosurefor 5 min. A heat source is positioned directly beneath a hindpaw andthe time taken for hindpaw withdrawal monitored automatically. If theanimal does not respond within 20 sec, the stimulus is automaticallyterminated to prevent tissue damage. Measurements for both the injuredand contralateral (control) hindpaw are recorded. Thermal hyperalgesiais evidenced by a shorter response latency by the injured as compared tothe control paw.

ED₅₀ values and their standard error of means (SEM) are determined usingaccepted numerical methods. For example, see R. E. Kirk (1982)“Experimental Design: Procedures for the behavioral sciences,” 2nd ed.

1-47. (canceled)
 48. A compound selected from the group consisting of(3S, 4aR, 6S, 8aR)6-(3-Carboxy-naphthalen-2-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-(4-carboxy-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; ethyl (3S, 4aR, 6S, 8aR)6-(4-ethoxycarbonyl-biphenyl-3-yloxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate;(3S, 4aR, 6S, 8aR)6-(2-carboxy-5-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; ethyl (3S, 4aR, 6S, 8aR)6-(5-chloro-2-ethoxycarbonyl-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate;(3S, 4aR, 6S, 8aR)6-(2-carboxy-4,5-difluoro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-(2-carboxy-4-chloro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-(2-carboxy-4-nitro-phenoxy)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[3-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[4-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[4-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-bromo-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[3,5-difluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[4-chloro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-methyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-methoxy-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-Benzyloxy-3-fluoro-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-((3-carboxy-2-naphthalenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-(2-(1(2)H-tetrazolylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-((2-carboxy-5-methylphenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-((2-carboxy-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-((2-carboxy-4-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; Ethyl(3S, 4aR, 6S, 8aR)6-((2-ethoxycarbonyl-5-chlorophenyl)thio)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate;(3S, 4aR, 6S, 8aR)6-[5-Benzyl-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-(2-thienyl)-2-(1(2)H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S,4aR,6S,8aR)6-[2′-Fluoro-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S,4aR,6S,8aR)6-[4′-Methyl-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR,6S, 8aR)6-[5-Naphthalen-2-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S,4aR,6S,8aR)6-[2′-Methoxy-4-(2H-tetrazol-5-yl)-biphenyl-3-yloxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-Pyrazol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; (3S, 4aR, 6S, 8aR)6-[5-indol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid; and (3S, 4aR, 6S, 8aR)6-[5-Pyrrol-1-yl-2-(2H-tetrazol-5-yl)-phenoxy]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid, or a pharmaceutically acceptable salt thereof.